Methods for treating asthmatic conditions

ABSTRACT

This invention provides methods for treating in mammals asthma and asthmatic conditions using substituted indole compounds of the general formula:  
                 
 
     and pharmaceutically acceptable salt forms thereof, and methods for using the compounds as inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A 2  enzymes, and for the medical treatment, prevention and inhibition of pain and inflammation.

[0001] The present invention relates tomethods of treating oralleviating asthma and the symptoms of asthma utilizing chemicalinhibitors of the activity of various phospholipase enzymes,particularly cytosolic phospholipase A₂ enzymes (cPLA₂), moreparticularly including inhibitors of cytosolic phospholipase A₂ alphaenzymes (cPLA_(2α)).

BACKGROUND OF THE INVENTION

[0002] Leukotrienes and prostaglandins are important mediators ofinflammation, each of which contributes to the development of aninflammatory response in a different way. Leukotrienes recruitinflammatory cells such as neutrophils to an inflamed site, promote theextravasation of these cells and stimulate release of superoxide andproteases which damage the tissue. Leukotrienes also play apathophysiological role in the hypersensitivity experienced byasthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)].Prostaglandins enhance inflammation by increasing blood flow andtherefore infiltration of leukocytes to inflamed sites. Prostaglandinsalso potentiate the pain response induced by stimuli.

[0003] Prostaglandins and leukotrienes are unstable and are not storedin cells, but are instead synthesized [W. L. Smith, Biochem. J.,259:315-324 (1989)] from arachidonic acid in response to stimuli.Prostaglandins are produced from arachidonic acid by the action of COX-1and COX-2 enzymes. Arachidonic acid is also the substrate for thedistinct enzyme pathway leading to the production of leukotrienes.

[0004] Arachidonic acid which is fed into these two distinctinflammatory pathways is released from the sn-2 position of membranephospholipids by phospholipase A₂ enzymes (hereinafter PLA₂). Thereaction catalyzed by PLA₂ is believed to represent the rate-limitingstep in the process of lipid mediated biosynthesis and the production ofinflammatory prostaglandins and leukotrienes. When the phospholipidsubstrate of PLA₂ is of the phosphotidyl choline class with an etherlinkage in the sn-1 position, the lysophospholipid produced is theimmediate precursor of platelet activating factor (hereafter calledPAF), another potent mediator of inflammation [S. I. Wasserman, HospitalPractice, 15:49-58 (1988)].

[0005] Most anti-inflammatory therapies have focused on preventingproduction of either prostglandins or leukotrienes from these distinctpathways, but not on all of them. For example, ibuprofen, aspirin, andindomethacin are all NSAIDs which inhibit the production ofprostaglandins by COX-1/COX-2 inhibition, but have no effect on theinflammatory production of leukotrienes from arachidonic acid in theother pathways. Conversely, zileuton inhibits only the pathway ofconversion of arachidonic acid to leukotrienes, without affecting theproduction of prostaglandins. None of these widely-usedanti-inflammatory agents affects the production of PAF.

[0006] Consequently the direct inhibition of the activity of PLA₂ hasbeen suggested as a useful mechanism for a therapeutic agent, i.e., tointerfere with the inflammatory response. [See, e.g., J. Chang et al,Biochem. Pharmacol., 36:2429-2436 (1987)].

[0007] A family of PLA₂ enzymes characterized by the presence of asecretion signal sequenced and ultimately secreted from the cell havebeen sequenced and structurally defined. These secreted PLA₂s have anapproximately 14 kD molecular weight and contain seven disulfide bondswhich are necessary for activity. These PLA₂s are found in largequantities in mammalian pancreas, bee venom, and various snake venom.[See, e.g., references 13-15 in Chang et al, cited above; and E. A.Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreaticenzyme is believed to serve a digestive function and, as such, shouldnot be important in the production of the inflammatory mediators whoseproduction must be tightly regulated.

[0008] The primary structure of the first human non-pancreatic PLA₂ hasbeen determined. This non-pancreatic PLA₂ is found in platelets,synovial fluid, and spleen and is also a secreted enzyme. This enzyme isa member of the aforementioned family. [See, J. J. Seilhamer et al, J.Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem.,264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm.,163:42-48 (1989)]. However, it is doubtful that this enzyme is importantin the synthesis of prostaglandins, leukotrienes and PAF, since thenon-pancreatic PLA₂ is an extracellular protein which would be difficultto regulate, and the next enzymes in the biosynthetic pathways for thesecompounds are intracellular proteins. Moreover, there is evidence thatPLA₂ is regulated by protein kinase C and G proteins [R. Burch and J.Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which arecytosolic proteins which must act on intracellular proteins. It would beimpossible for the non-pancreatic PLA₂ to function in the cytosol, sincethe high reduction potential would reduce the disulfide bonds andinactivate the enzyme.

[0009] A murine PLA₂ has been identified in the murine macrophage cellline, designated RAW 264.7. A specific activity of 2 mols/min/mg,resistant to reducing conditions, was reported to be associated with theapproximately 60 kD molecule. However, this protein was not purified tohomogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta.,963:476-492 (1988)]. The references cited above are incorporated byreference herein for information pertaining to the function of thephospholipase enzymes, particularly PLA₂.

[0010] A cytosolic phospholipase A₂ alpha (hereinafter “cPLA₂α”) hasalso been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and5,354,677, which are incorporated herein by reference as if fully setforth. The enzyme of these patents is an intracellular PLA₂ enzyme,purified from its natural source or otherwise produced in purified form,which functions intracellularly to produce arachidonic acid in responseto inflammatory stimuli.

[0011] Now that several phospholipase enzymes have been identified, itwould be desirable to identify chemical inhibitors of the action ofspecific phospholipase enzymes, which inhibitors could be used to treatinflammatory conditions, particularly where inhibition of production ofprostaglandins, leukotrienes and PAF are all desired results. Thereremains a need in the art for an identification of suchanti-inflammatory agents for therapeutic use in a variety of diseasestates.

DETAILED DESCRIPTION OF THE INVENTION

[0012] This invention comprises a method of treatment, inhibition,alleviation or relief of asthma and asthmatic conditions in a mammal,preferably in a human, the method comprising administering to a mammalin need thereof a pharmaceutically effective amount of a compound of theformula:

[0013] wherein:

[0014] R is selected from the formulae —(CH₂)_(n)—A, —(CH₂)_(n)—S—A, or—(CH₂)_(n)—O—A, wherein A is selected from the moieties:

[0015] wherein

[0016] D is C₁-C₆ lower alkyl, C₁-C₆ lower alkoxy, C₃-C₆ cycloaklyl —CF₃or —(CH₂)₁₋₃—CF₃;

[0017] B and C are independently selected from phenyl, pyridinyl,pyrimidinyl, furanyl, thiophenyl or pyrrolyl groups, each optionallysubstituted by from 1 to 3, preferably 1 to 2, substituents selectedindependently from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆),—NO₂, or by a 5- or 6-membered heterocyclic or heteroaromatic ringcontaining 1 or 2 heteroatoms selected from O, N or S; or

[0018] n is an integer from 0 to 3;

[0019] n₁ is an integer from 1 to 3;

[0020] n₂ is an integer from 0 to 4;

[0021] n₃ is an integer from 0 to 3;

[0022] n₄ is an integer from 0 to 2;

[0023] X₁ is selected from a chemical bond, —S—, —O—, —S(O)—, —S(O)₂—,—NH—, —NHC(O)—C═C—,

[0024] R₁ is a moiety selected from C₁-C₆ alkyl, C₁-C₆ fluorinatedalkyl, C₃-C₆ cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN,—N(C₁-C₆ alkyl)₂, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl,napthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl,imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazole,indole, benzoxazole, benzofuran, imidazolidine-2-thione,7,7,dimethyl-bicyclo[2.2.1]heptan-2-one, Benzo[1,2,5]oxadiazole,2-Oxa-5-aza-bicyclo[2.2.1]heptane, Piperazin-2-one or pyrrolyl groups,each optionally substituted by from 1 to 3, preferably 1 to 2,substituents independently selected from H, halogen, —CN, —CHO, —CF₃,OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —SO₂(C₁-C₃ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₃ alkyl),—SO₂N(C₁-C₃ alkyl)₂, —COOH, —CH₂—COOH, —CH₂—N(C₁-C₆ alkyl), —CH₂—N(C₁-C₆alkyl)₂, —CH₂—NH₂, pyridine, 2-Methyl-thiazole, morpholino,1-Chloro-2-methyl-propyl, —C₁-C₆thioalkyl, phenyl (further optionallysubstituted with halogens), benzyloxy, (C₁-C₃ alkyl)C(O)CH₃, (C₁-C₃alkyl)OCH₃, C(O)NH₂, or

[0025] X₂ is selected from —O—, —CH₂—, —S—, —SO—, —SO₂—, —NH—, —C(O)—,

[0026] R₂ is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl,furyl, thienyl or pyrrolyl groups, the ring moiety being substituted bya group of the formula —(CH₂)_(n4)—CO₂H or a pharmaceutically acceptableacid mimic or mimetic; and also optionally substituted by 1 or 2additional substituents independently selected from H, halogen, —CN,—CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl,—NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

[0027] R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH,—C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

[0028] R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH,—C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), —NO₂, —N—C(O)—N(C₁-C₃ alkyl)₂,—N—C(O)—NH(C₁-C₃ alkyl), —N—C(O)—O—(C₁-C₃ alkyl), —SO₂—C₁-C₆ alkyl,—S—C₃-C₆ cycloalkyl, —S—CH₂—C₃-C₆ cycloalkyl, —SO₂—C₃-C₆ cycloalkyl, ,—SO₂—CH₂—C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl,—O—C₃-C₆ cycloalkyl, , —O—CH₂—C₃-C₆ cycloalkyl, phenyl, benzyl,benzyloxy, morpholino or other heterocycles such as pyrrolidino,piperidine, piperizine furan, thiophene, imidazole, tetrazole, pyrazine,pyrazolone, pyrazole, imidazole, oxazole or isoxazole, the rings of eachof these R₄ groups each being optionally substituted by from 1 to 3substituents selected from the group of H, halogen, —CN, —CHO, —CF₃,—OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —SO₂(C₁-C₃ alkyl), —SO₂NH(C₁-C₃ alkyl),—SO₂N(C₁-C₃ alkyl)₂, or OCF₃;

[0029] or a pharmaceutically acceptable salt form thereof.

[0030] It will be understood that the C₁-C₆ fluorinated alkyl groups inthe definition of R₁ may be any alkyl group of 1 to 6 carbon atoms withany amount of fluorine substitution including, but not limited to, —CF₃,alkyl chains of 1 to 6 carbon atoms terminated by a trifluoromethylgroup, —CF₂CF₃, etc.

[0031] Ester forms of the present compounds include the pharmaceuticallyacceptable ester forms known in the art including those which can bemetabolized into the free acid form, such as a free carboxylic acidform, in the animal body, such as the corresponding alkyl esters,cycloalkyl esters, aryl esters and heterocyclic analogues thereof can beused according to the invention, where alkyl esters, cycloalkyl estersand aryl esters are preferred and the alcoholic residue can carryfurther substituents. C₁-C₈ alkyl esters, preferably C₁-C₆ alkyl esters,such as the methyl ester, ethyl ester, propyl ester, isopropyl ester,butyl ester, isobutyl ester, t-butyl ester, pentyl ester, isopentylester, neopentyl ester, hexyl ester, cyclopropyl ester,cyclopropylmethyl ester, cyclobutyl ester, cyclopentyl ester, cyclohexylester, or aryl esters such as the phenyl ester, benzyl ester or tolylester are particularly preferred.

[0032] In the definition of X₁, the alkenyl bridging group —C═C— isunderstood to indicate either the cis or trans orientation of theindicated compound(s).

[0033] Pharmaceutically acceptable acid mimics or mimetics useful in thecompounds of this invention include those wherein R₂ is selected fromthe group of:

[0034] wherein R_(a) is selected from —CF₃, —CH₃, phenyl, or benzyl,with the phenyl or benzyl groups being optionally substituted by from 1to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl,—CF₃, halogen, —OH, or —COOH; R_(b) is selected from —CF₃, —CH₃, —NH₂,phenyl, or benzyl, with the phenyl or benzyl groups being optionallysubstituted by from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, —CF₃, halogen, —OH, or —COOH; and R_(c) isselected from —CF₃ or C₁-C₆ alkyl.

[0035] The methods of treatment, inhibition, alleviation or relief ofasthma and asthmatic conditions of this invention include those forExtrinsic Asthma (also known as Allergic Asthma or Atopic Asthma),Intrinsic Asthma (also known as Nonallergic Asthma or Nonatopic Asthma)or combinations of both, which has been referred to as Mixed Asthma. Themethods for those experiencing or subject to Extrinsic or AllergicAsthma include incidents caused by or associated with many allergens,such as pollens, spores, grasses or weeds, pet danders, dust, mites,etc. As allergens and other irritants present themselves at varyingpoints over the year, these types of incidents are also referred to asSeasonal Asthma. Also included in the group of Extrinsic Asthmas isbronchial asthmas and allergic bronchopulminary aspergillosis.

[0036] Intrinsic Asthmas that may be treated or alleviated by thepresent methods include those caused by infectious agents, such as coldand flu viruses in adults and respiratory syncytial virus (RSV),rhinovirus and influenza viruses common in children. Also included arethe asthma conditions which may be brought about in some asthmatics byexercise and/or cold air. The methods are useful for Intrinsic Asthmasassociated with industrial and occupational exposures, such as smoke,ozone, noxious gases, sulfur dioxide, nitrous oxide, fumes, includingisocyanates, from paint, plastics, polyurethanes, varnishes, etc., wood,plant or other organic dusts, etc. The methods are also useful forasthmatic incidents associated with food additives, preservatives orpharmacological agents. Common materials of these types are foodcoloring such as Tartrazine, preservatives like bisulfites andmetabisulfites, and pharmacological agents such as aspirin andnon-steroidal anti-inflammatory agents (NSAIDs). Also included aremethods for treating, inhibiting or alleviating the types of asthmareferred to as Silent Asthma or Cough Variant Asthma.

[0037] The methods herein are also useful for treatment and alleviationof Intrinsic Asthma associated with gastroesophageal reflux (GERD),which can stimulate bronchoconstriction. GERD, along with retainedbodily secretions, suppressed cough, and exposure to allergens andirritants in the bedroom can contribute to asthmatic conditions and havebeen collectively referred to as Nighttime Asthma or Nocturnal Asthma.In methods of treatment, inhibition or alleviation of asthma associatedwith GERD, a pharmaceutically effective amount of the compounds of thisinvention may be used as described herein in combination with apharmaceutically effective amount of an agent for treating GERD. Theseagents include, but are not limited to, proton pump inhibiting agentslike PROTONIX® brand of delayed-release pantoprazole sodium tablets,PRILOSEC® brand omeprazole delayed release capsules, ACIPHEX® brandrebeprazole sodium delayed release tablets or PREVACID® brand delayedrelease lansoprazole capsules. Pharmaceutically effective amounts ofthese agents are understood to include those described in theconventional medical literature, including the pharmaceuticallyeffective doses and regimens for these agents described in the 2001Physicians' Desk Reference (55 Edition), published by Medical EconomicsCompany, Montvale, N.J. 07645-1742.

[0038] A first subgroup of compoundsuseful in the methods of thisinvention, or a pharmaceutically acceptable salt thereof, include thoseof the group above wherein A is the moiety:

[0039] and B, C, n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are asdefined above.

[0040] A second subgroup of compoundsuseful in the methods of thisinvention comprises those of the first subgroup, above, wherein B and Care unsubstituted phenyl, pyridinyl, pyrimidinyl, furyl, thienyl orpyrrolyl groups and R, n, n1, n2, n3, n4, R₁, X₁, X₂, R₂, R₃, and R₄ areas defined above.

[0041] A third subgroup of compounds and pharmaceutically acceptablesalt formsuseful in the methods of this invention comprise those of thesecond subgroup, above, wherein A is the moiety:

[0042] and n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are asdefined above.

[0043] A fourth subgroup of compoundsuseful in the methods of thisinvention comprises those of the formulae (II) or (III):

[0044] wherein n1, n2, n3, n4, X₁, X₂, R₁, R₂, R₃, and R₄ are as definedabove, or a pharmaceutically acceptable salt thereof.

[0045] A fifth subgroup of compoundsuseful in the methods of thisinvention includes those of formulae (II) or (III) wherein n3=1, and n1,n2, n4, X₁, X₂, R₁, R₂, R₃, and R₄ are as defined above, or apharmaceutically acceptable salt thereof.

[0046] A sixth subgroup of compoundsuseful in the methods of thisinvention includes those of the fifth subgroup, above, wherein R₂ isphenyl substituted by a group of the formula —(CH₂)_(n4)—CO₂H; andoptionally substituted by 1 or 2 additional substituents independentlyselected from H, halogen, —CN, —CHO, —CF₃, —OH,—C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆),or —NO; and n1, n2, n4, R₁, X₁, X₂, R₂, R₃, and R₄ are as defined above,or a pharmaceutically acceptable salt thereof.

[0047] A seventh subgroup of compoundsuseful in the methods of thisinvention comprises those of the formulae (IV) or (V):

[0048] wherein:

[0049] n₁ is an integer from 1 to 3;

[0050] n₂ is an integer from 1 to 3;

[0051] R₅, R₆ and R₇ are independently selected from H, halogen, —CN,—CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

[0052] X₁ is selected from a chemical bond, —S—, —O—, —NH— or —N(C₁-C₃alkyl)-;

[0053] X₂ is selected from —O—, —SO₂— or —CH₂—;

[0054] R₂ is a moiety selected from the group of:

[0055] R₈ and R₉ are independently selected from H, halogen, —CN, —CHO,—CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂;

[0056] n₄ is an integer from 0 to 2;

[0057] R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; and

[0058] R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine, furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole;

[0059] or a pharmaceutically acceptable salt form thereof.

[0060] An eighth subgroup of compoundsuseful in the methods of thisinvention include those of the formulae (VI) or (VII):

[0061] wherein:

[0062] X₁ is selected from a chemical bond, —S—, —O—, —NH— or —N(C₁-C₃alkyl)-;

[0063] X₂ is selected from —O—, —SO₂—, or —CH₂—;

[0064] R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; and

[0065] R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine, furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole;

[0066] n₁ is an integer from 1 to 2;

[0067] n₂ is an integer from 1 to 2;

[0068] R₅, R₆ and R₇ are independently selected from H, halogen, —CN,—CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

[0069] R₈ and R₉ are independently selected from H, halogen, —CN, —CHO,—CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂;

[0070] or a pharmaceutically acceptable salt form thereof.

[0071] A ninth subgroup of compounds useful in the methods of thisinvention include those of formulae (VI) or (VII) wherein: n₁ is 1; n₂is 1; and X₁, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are as defined in theeighth subgroup, above, or a pharmaceutically acceptable salt formthereof.

[0072] A tenth subgroup useful in the methods of this inventioncomprises the compounds of the ninth subgroup, above, wherein X₁ is achemical bond and n₁, n₂, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are asdefined in the ninth subgroup, above, or a pharmaceutically acceptablesalt form thereof.

[0073] A further method of treatment of asthma of this inventioncomprises administering to a mammal in need of such treatment apharmaceutically effective amount of a compound of this invention, asdescribed above, and a pharmaceutically effective amount of one or moreadditional anti-asthma agents.

[0074] Anti-asthma agents useful with these combinations includelong-term-control medications, such as corticosteroids(glucocorticoids), cromolyn sodium (disodium cromoglycate—DSCG),nedocromil, methylxanthines (such as theophylline) and leukotrienemodifiers. Useful leukotriene modifiers include leukotriene receptorantagonists, such as zafirlukast (ACCOLATE®) and monetlukast(SINGULAIR®), and 5-lipoxygenase inhibitors, such as zileuton (ZYFLO®).Useful corticosteroids include inhaled products, such as Beclomethasonedipropionate, Budesonide, Flunisolide, Fluticasone, and Triamcinolone,as well as the pharmaceutically acceptable salt forms thereof. Alsouseful are systemic corticosteroids such as prednisone, prednisolone andmethylprednisolone.

[0075] Also useful are quick-relief anti-asthma medications, such aslong-acting beta₂-agonists, short-acting beta₂-agonists,anticholinergics and systemic corticosteroids. β-Adrenergic agents whichmay be used include epinephrine, isoproterenol, metaproterenol,terbutaline, isoetharine, albuterol, bitolterol and perbuterol. Usefulanticholinergic agents include atropine (and its derivative ipatropiumbromide) and glycopyrrolate. The compounds of this invention may also beused to treat asthma in conjunction with allergy immunotherapies, whichalso referred to in the art as hyposensitization therapies. Thesecompounds may be administered according to the dosages and regimensknown in the art.

[0076] Additional anti-asthma agents which may be used in thecombinations of this invention include pranlukast, anakinra,seratrodast, olopatadine hydrochloride, cromoglicate lisetil,ramatroban, interleukin-4 receptor (Immunex), urodilatin, colforsindaropate, salbutamol, LCB-2183, andolast, ciclesonide, budesonide,formoterol, omalizumab, tranilast, saredutant, CDP-835 (anti-IL-5 Mab),fexofenadine HCl, N-(1-(Chlorophenyl)-1-methylethyl)-3-(imidazol-1-yl)propylaminedihydrochloride (BTS-71-321), cilomilast, bimosiamose,Corticotropin-releasing factor, clenoliximab, tiotropium bromide,2H-1,2-Benzoselenazine, 3,4-dihydro-4,4-dimethyl (BXT-51072),atreleuton, (R)-salbutamol,8-Methoxyquinoline-5-(N-(2,5-dichloropyridin-3-yl)) carboxamide(D-4418), triamcinolone acetonide, KW-4490 (KF-19514), LAX-300 (LX-109),IDEC-152 (ST-152; anti-CD23 antibody), cytokine Traps, anandamide,SRL-172, salmeterol+Fluticasone, KCA-757, 2-Pyridinecarboxylic acid,6-(2-(3,4-diethoxyphenyl)-4-thiazolyl)-(OPC-6535), PM-56D9, salbutamol,CT-2820 (PDEIV inhibitors), beclometasone, nepadutant, ketotifenfumarate, DHEAS (PB-005), Pharmaprojects No.5163, No. 5278 and No. 5297,salbutamol sulfate, EPI-2010 (EpiGenRx), mepolizumab, Benzamide,N-(5-(3-((4-chlorophenyl)sulfonyl)propyl)-2-(1H-tetrazol-5-ylmethoxy)phenyl)-3-((4-(1,1-dimethylethyl)-2-thiazolyl)methoxy)-,monosodium salt (YM-158),2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydro-pyridazin-3-onePharmaprojects (No.5450), Sch-205528, L-826141 (Pharmaprojects No.5477), Budesonide, duramycin,4,4-Bis(4-(quinolin-2-ylmethoxy)phenyl)pentanoic acid sodium salt(VML-530), IL-9 inhibitor, beclometasone dipropionate, formoterol,cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD-7349), salbutamol,Ethanaminium,2-(((2-acetyl-4-((1-oxohexadecyl)amino) phenoxy)hydroxyphosphinyl)oxy)-N, N, N-trimethyl-, inner salt (CPR-2015),PD-168787 (Cl-1018), cathepsin S inhibitors, SB-240683 (anti-IL-4 Mab),BIIL-284, APC-2059, budesonide+formoterol, Bay-16-9996 (IL-4antagonist), beclometasone, GW-328267, VLA-4 antagonists,4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone(TA-270), CpG-7909 (ProMune), DNK-333A (Pharmaprojects No. 6070),AWD-12-281, LM-1507 (LM-1484), formoterol, MOL-6131, cathepsin Sinhibitors, CS-615, ibudilast,2-{N-(4-(4-Chlorophenylsulfonylamino)butyl)-N-{3-(2-(4-cyclobutylthiazol-2-yl)ethyl)benzyl}sulfamoyl}benzoicacid (S-36527), and2-{N-(4-(4-Chlorophenylsulfonylamino)butyl)-N-{3-((4-isopropylthiazol-2-yl)methyloxy)benzyl}sulfamoyl}benzoicacid (S-36496).

[0077] This invention also provides pharmaceutical compositions usefulin the methods herein comprising a pharmaceutically effective amount ofa compound of this invention, or a pharmaceutically acceptable salt formthereof, and one or more pharmaceutically acceptable carriers orexcipients.

[0078] Compounds of the present invention may be used in apharmaceutical composition when combined with a pharmaceuticallyacceptable carrier. Such a composition may also contain (in addition toa compound or compounds of the present invention and a carrier)diluents, fillers, salts, buffers, stabilizers, solubilizers, and othermaterials well known in the art. The term “pharmaceutically acceptable”means a non-toxic material that does not interfere with theeffectiveness of the biological activity of the active ingredient(s).The characteristics of the carrier will depend on the route ofadministration. The pharmaceutical composition may further contain otheranti-inflammatory agents. Such additional factors and/or agents may beincluded in the pharmaceutical composition to produce a synergisticeffect with compounds of the present invention, or to minimize sideeffects caused by the compound of the present invention.

[0079] The pharmaceutical composition of the invention may be in theform of a liposome in which compounds of the present invention arecombined, in addition to other pharmaceutically acceptable carriers,with amphipathic agents such as lipids which exist in aggregated form asmicelles, insoluble monolayers, liquid crystals, or lamellar layers inaqueous solution. Suitable lipids for liposomal formulation include,without limitation, monoglycerides, diglycerides, sulfatides,lysolecithin, phospholipids, saponin, bile acids, and the like.Preparation of such liposomal formulations is within the level of skillin the art, as disclosed, for example, in U.S. Pat. No. 4,235,871; U.S.Pat. No. 4,501,728; U.S. Pat. No. 4,837,028; and U.S. Pat. No.4,737,323, all of which are incorporated herein by reference.

[0080] As used herein, the terms “pharmaceutically effective amount” or“therapeutically effective amount” as used herein means the total amountof each active component of the pharmaceutical composition or methodthat is sufficient to show a meaningful patient benefit, i.e.,treatment, healing, prevention, inhibition or amelioration of aphysiological response or condition, such as an inflammatory conditionor pain, or an increase in rate of treatment, healing, prevention,inhibition or amelioration of such conditions. When applied to anindividual active ingredient, administered alone, the term refers tothat ingredient alone. When applied to a combination, the term refers tocombined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially orsimultaneously.

[0081] Each of the methods of treatment or use of the present invention,as described herein, comprises administering to a mammal in need of suchtreatment or use a pharmaceutically or therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt form thereof. Compounds of the present invention may beadministered in accordance with the method of the invention either aloneor in combination with other therapies such as treatments employingother anti-inflammatory agents, cytokines, lymphokines or otherhematopoietic factors. When co-administered with one or more otheranti-inflammatory agents, cytokines, lymphokines or other hematopoieticfactors, compounds of the present invention may be administered eithersimultaneously with the other anti-inflammatory agent(s), cytokine(s),lymphokine(s), other hematopoietic factor(s), thrombolytic oranti-thrombotic factors, or sequentially. If administered sequentially,the attending physician will decide on the appropriate sequence ofadministering compounds of the present invention in combination withother anti-inflammatory agent(s), cytokine(s), lymphokine(s), otherhematopoietic factor(s), thrombolytic or anti-thrombotic factors.

[0082] Administration of compounds of the present invention used in thepharmaceutical composition or to practice the method of the presentinvention can be carried out in a variety of conventional ways, such asoral ingestion, inhalation, or cutaneous, subcutaneous, or intravenousinjection.

[0083] When a therapeutically effective amount of compounds of thepresent invention is administered orally, compounds of the presentinvention will be in the form of a tablet, capsule, powder, solution orelixir. When administered in tablet form, the pharmaceutical compositionof the invention may additionally contain a solid carrier such as agelatin or an adjuvant. The tablet, capsule, and powder contain fromabout 5 to 95% compound of the present invention, and preferably fromabout 25 to 90% compound of the present invention. When administered inliquid form, a liquid carrier such as water, petroleum, oils of animalor plant origin such as peanut oil, mineral oils, phospholipids, tweens,triglycerides, including medium chain triglycerides, soybean oil, orsesame oil, or synthetic oils may be added. The liquid form of thepharmaceutical composition may further contain physiological salinesolution, dextrose or other saccharide solution, or glycols such asethylene glycol, propylene glycol or polyethylene glycol. Whenadministered in liquid form, the pharmaceutical composition containsfrom about 0.5 to 90% by weight of compound of the present invention,and preferably from about 1 to 50% compound of the present invention.

[0084] When a therapeutically effective amount of compounds of thepresent invention is administered by intravenous, cutaneous orsubcutaneous injection, compounds of the present invention will be inthe form of a pyrogen-free, parenterally acceptable aqueous solution.The preparation of such parenterally acceptable protein solutions,having due regard to pH, isotonicity, stability, and the like, is withinthe skill in the art. A preferred pharmaceutical composition forintravenous, cutaneous, or subcutaneous injection should contain, inaddition to compounds of the present invention, an isotonic vehicle suchas Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, orother vehicle as known in the art. The pharmaceutical composition of thepresent invention may also contain stabilizers, preservatives, buffers,antioxidants, or other additives known to those of skill in the art.

[0085] The amount of compound(s) of the present invention in thepharmaceutical composition of the present invention will depend upon thenature and severity of the condition being treated, and on the nature ofprior treatments the patient has undergone. Ultimately, the attendingphysician will decide the amount of compound of the present inventionwith which to treat each individual patient. Initially, the attendingphysician will administer low doses of compound of the present inventionand observe the patient's response. Larger doses of compounds of thepresent invention may be administered until the optimal therapeuticeffect is obtained for the patient, and at that point the dosage is notincreased further. It is contemplated that the various pharmaceuticalcompositions used to practice the method of the present invention shouldcontain about 0.1 μg to about 100 mg (preferably about 0.1 mg to about50 mg, more preferably about 1 mg to about 2 mg) of compound of thepresent invention per kg body weight.

[0086] The duration of intravenous therapy using the pharmaceuticalcomposition of the present invention will vary, depending on theseverity of the disease being treated and the condition and potentialidiosyncratic response of each individual patient. It is contemplatedthat the duration of each application of the compounds of the presentinvention will be in the range of 12 to 24 hours of continuousintravenous administration. Ultimately the attending physician willdecide on the appropriate duration of intravenous therapy using thepharmaceutical composition of the present invention.

[0087] A preferred lipid based oral formulation of this invention hasbeen prepared by blending 50% PHOSOL® 53MCT (American Lecithin Company),5% Polysorbate 80, 15% LABRASOL® Caprylocaproyl macrogol-8 glycerides(Gattefosse Corp.), 15% Propylene Carbonate and 15% active cPLA2inhibiting compound(s) of this invention, each percentage listed beingby weight.

[0088] This invention can be further understood by the followingnon-limiting specific examples.

[0089] Method A

[0090] The initial indole of Method A may be alkylated at the C3position (the carbon atom at the 3-position of the indole moiety) withaldehydes or the corresponding acetals in the presence of a Lewis orBronsted acid, such as boron triflouride etherate or trifluoroaceticacid. The indole nitrogen may then be alkylated by treatment with astrong base such as sodium bis(trimethylsilyl) amide, n-BuLi, sodiumhydride or potassium hydride in a solvent such as DMF, DMSO or THFfollowed by exposure to the appropriate alkyl halide. The resultingproduct can be treated with carbon tetrabromide in carbon tetrachlorideand a catalytic amount of benzoyl peroxide to effect dibromination ofthe C2 methyl group. The dibromide can then either be stirred withsilver carbonate in acetone water or poured into DMSO and stirred. Bothof these procedures generate the aldehyde which is then subjected to thenitro aldol reaction with nitromethane and a catalytic amount ofammonium acetate at reflux. The resulting vinyl nitro intermediate isreduced to the amine upon treatment with zinc mercury amalgam in amixture of THF and conc. HCL at reflux. This amine can then be treatedwith the requisite sulfonyl chloride under biphasic conditions, aqueoussodium bicarbonate/dichloromethane, or in organic solvent with theaddition of a hindered organic amine base. The final hydrolysis wasaccomplished under basic conditions with sodium hydroxide in water andmethanol and THF at room temperature or at elevated temperature.Alternatively it may be cleaved by treatment with sodium thiomethoxidein a solvent such as THF or DMF at elevated temperatures (50° C.-100°C.). This method was used in the synthesis of Examples 1-88, 108-112,and 126-128.

[0091] Method B

[0092] The initial halide of Method B is refluxed in aqueous sodiumsulfite and a suitable cosolvent if necessary, such as alcohol, dioxaneetc, for the required amount of time to form the desired sodiumsulfonate. This intermediate was treated with thionyl chloride,phosphorous pentachloride or oxalyl chloride, in dichloromethane with asmall amount of DMF and stirred for several hours at room temperatureuntil the sulfonyl chloride is formed. The thus formed sulfonyl chlorideis then used crude in Method A. This method was used in the synthesis ofExamples 1-88, 108-112 and 126-128 when the sulfonyl chloride was notcommercially available.

EXAMPLE 14-[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0093] This synthesis is depicted in Method A.

[0094] Step 1: To 4-hydroxy-benzoic acid methyl ester (1.0 eq) in DMF(0.83 M) was added K₂CO₃ (2.0 eq) followed by2-bromo-1,1-diethoxy-ethane and the reaction mixture was stirred at 110°C. for 2 days. TLC showed a new spot. The reaction mixture was dilutedwith ethyl acetate, washed with 1N NaOH, water, and brine, dried oversodium sulfate, and solvent was removed to afford desired product in 84%yield. This material was used in the next step without furtherpurification.

[0095] Step 2: To the above product (1.0 eq) and 5-chloro-2-methylindole (1.0 eq) in CH₂Cl₂ (0.12 M) was added triethylsilane (3.0 eq)followed by trifluoroacetic acid (3.0 eq). After being stirred overnightat room temperature, added water and trifluroacetic acid (1.0 eq) to thereaction mixture, stirred at room temperature for two days, diluted withCH₂Cl₂, washed with 1N NaOH, water, brine, dried over sodium sulfate.Trituration of the material with CH₂Cl₂ and hexanes afforded the C3alkylated indole in 92% yield

[0096] Step 3: To the indole from above (1.0 eq) in DMF (0.36 M) at 25°C. was added NaH (1.2 eq, 60% dispersion in oil), and the brown solutionwas stirred at 0 to −5° C. for 1 h and then compoundbromodiphenylmethane was added (1.1 eq), and then the reaction mixturewas stirred overnight. It was then quenched with water, diluted withethyl acetate, washed with water and brine, dried over sodium sulfateand purified by column chromatography to yield 72% of the desiredproduct.

[0097] Step 4: To the N-alkylated indole from above (1.0 eq) in CCl₄(0.2 M) was added N-bromosuccinimide (2.0 eq) and a catalytic amount ofbenzoyl peroxide. The solution was heated to reflux for 3 h, cooled to25° C., filtered, and the solid was washed with CCl₄. The filtrate wasconcentrated to a foam, which was dried. The foam was dissolved inacetone, and Ag₂CO₃ (1.1 eq.) was added followed by water and thereaction mixture was stirred overnight at room temperature. It wasfiltered and washed with acetone. The filtrate was concentrated to aresidue, to which was added water. This mixture was extracted with ethylacetate, washed with brine, dried over sodium sulfate and thenchromatographic purification on the residue gave the desired product in85% yield. Alternatively the dibromide from the reaction with NBS couldbe poured into DMSO (10-20% concentration by weight) stirred for 30minutes at room temperature. When the reaction was deemed complete itwas poured into water and the resulting precipitate was isolated byfiltration, the cake was washed with water and dried to yield anessentially quantitative yield.

[0098] Step 5: To the above aldehyde (1.0 equiv) in CH₃NO₂ (0.2 M) wasadded ammonium acetate (4 equiv) and the resulting mixture was heated toreflux for 4 h. The reaction mixture was then diluted with EtOAc andwashed with brine. The aqueous phase was extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated until an orange crystalline solidprecipitated. The mixture was refrigerated overnight and the nitroolefin(76% yield) was collected by filtration. Evaporation of the solutionphase and purification of the residue by column chromatography (gradientelution 100% toluene→1% EtOAc-toluene) afforded an additional amount ofthe nitroolefin (23% yield).

[0099] Step 6: Zinc dust (20 equiv) was suspended in 5% aqueous HClsolution (8 M Zn/5% HCl). To this mixture was added HgCl₂ (0.28 equiv).The mixture was shaken for 10 min, the aqueous phase was decanted andreplaced with fresh 5% HCl, and again the mixture was shaken for 5 minand the aqueous phase was removed. The zinc-mercury amalgam thusgenerated was then added to a mixture of the nitroolefin (1.0 equiv) andconc. HCl (80 equiv) in THF (0.04 M nitroolefin/THF). The mixture wasmaintained at a gentle reflux for 1 h. The formation of product wasfollowed by TLC analysis. The mixture was cooled to room temperature andthe solids were removed by filtration through Celite. Conc. NH₄OH wasadded to the solution phase and the mixture was concentrated on therotary evaporator. The residue was dissolved in CH₂Cl₂ and conc. NH₄OH.The aqueous phase was extracted with CH₂Cl₂, and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated.Purification by column chromatography afforded the desired product (65%yield).

[0100] Step 7: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(1.0 equiv) and sat. NaHCO₃ (0.14 M) in CH₂Cl₂ (0.07 M) was added□-toluenesulfonyl chloride (1.0 equiv). After 1 h the mixture was pouredinto saturated sodium bicarbonate and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography (gradient elution using 20%EtOAc-hexanes→50% EtOAc-hexanes) to afford 86% of the desired product.

[0101] Step 8: The resulting ester was hydrolyzed by stirring with 1NNaOH (5 equiv) in THF (0.07 M) and enough MeOH to produce a clearsolution. The reaction was monitored by TLC (10% MeOH—CH₂Cl₂) for thedisappearance of starting material. The mixture was heated in a 60degrees C. oil bath for 2 hour. The mixture was concentrated, dilutedwith H₂O, and acidified to pH 2-4 using 1 M HCl. The aqueous phase wasextracted with EtOAc and the organic phase was washed with brine, driedover sodium sulfate, and concentrated to afford the desired product in92% yield. HRMS calc for [C₃₉H.₃₅ClN₂O₅.S+H] 679.2028 found 679.2031.

EXAMPLE 24-[2-(1-Benzhydryl-5-chloro-2-{2-[(isopropylsulfonyl)-amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0102] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and isopropylsulfonyl chloride according to theprocedure in Example 1 Step 7 in 55% yield.

[0103] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. HRMS calc for[C₃₅H.₃₅ClN₂O₅.S+H] 631.2028 found 631.2029.

EXAMPLE 34-[2-(1-Benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0104] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 1-butanesulfonyl chloride according to theprocedure in Example 1 Step 7 in 61% yield.

[0105] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₆H.₃₇ClN₂O₅.S+H] 645.2185 found 645.2185.

EXAMPLE 44-{2-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0106] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) (1.0 equiv) and Et₃N (3.0 equiv) or pyridine (3.0equiv) in CH₂Cl₂ (0.05 M) was added 1-methylimidazole-4-sulfonylchloride (1.2 equiv). The reaction was monitored by TLC (10%MeOH—CH₂Cl₂) and was heated if necessary. After 30 min the mixture waspoured into saturated sodium bicarbonate and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography to afford 92% of the desiredproduct.

[0107] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₆H.₃₃ClN₄O₅.S+H] 669.1933 found 669.1932.

EXAMPLE 54-{2-[1-Benzhydryl-2-(2-{[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

[0108] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-bromo-2-chloropyridine-5-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 74% yield.

[0109] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calc for[C₃₇H.₃₀BrCl₂N₃O₅.S+H] 778.0539 found 778.0544.

EXAMPLE 64-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0110] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and (1R)-(−)-10-camphorsulfonyl chloride according tothe procedure in Example 1 Step 7 in 77% yield.

[0111] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₄₂H₄₃ClN₂O₆.S+H] 739.2603 found 739.26.

EXAMPLE 74-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0112] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and (methanesulfonyl)methanesulfonyl chlorideaccording to the procedure in Example 4 Step 1 in 43% yield.

[0113] Step 2: The ester intermediate was hydrolyzed according toExample 117 Step 2 to afford the title acid in 95% yield. HRMS calc for[C₃₄H₃₃ClN₂O₇.S₂+H] 681.1491 found 681.1489.

EXAMPLE 84-(2-{1-Benzhydryl-5-chloro-2-[2-({[(2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0114] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and 2-(1-naphthyl)ethanesulfonyl chloride accordingto the procedure Example 1 Step 7 in 60% yield.

[0115] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₄H₃₉ClN₂O₅.S+H] 743.2341 found 743.2338.

EXAMPLE 94-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0116] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and 2-nitro-□-toluenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 82% yield.

[0117] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇.S+H] 724.1879 found 724.1877.

EXAMPLE 104-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0118] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [(3,4-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 82% yield.

[0119] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂ O₅.S+H] 747.1249 found 747.1249.

EXAMPLE 114-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0120] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [(3,5-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 100% yield.

[0121] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂ O₅.S+H] 747.1249 found 747.1249.

EXAMPLE 124-(2-{1-Benzhydryl-5-chloro-2-(2-({[(3-(trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0122] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [[3-(trifluoromethyl)-phenyl]methyl]sulfonylchloride according to the procedure in Example 1 Step 7 in 74% yield.

[0123] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂ O₅S+H] 747.1902 found 747.1904.

EXAMPLE 134-(2-{1-Benzhydryl-5-chloro-2-(2-({[(4-(trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0124] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [[4-(trifluoromethyl)phenyl]methyl]sulfonylchloride according to the procedure in Example 1 Step 7 in 77% yield.

[0125] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 83% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂ O₅S+H] 747.1902 found 747.1901.

EXAMPLE 144-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)-sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0126] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [(4-fluorophenyl)methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 Step 1 in 86% yield.

[0127] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₉H₃₄ClFN₂ O₅S+H] 697.1934 found 697.1938.

EXAMPLE 154-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0128] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and [(4-chlorophenyl-)methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 73% yield.

[0129] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂ O₅S+H] 713.1638 found 713.1643.

EXAMPLE 162-(2-{[(2-Aminobenzyl)sulfonyl]amino}ethyl)-4-{2-[1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

[0130] Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-{2-[2-nitrobenzyl]benzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate,Example 9, step 1, (1.0 equiv) in CH₂Cl₂ (0.014 M) was added a mixtureof tin(II) chloride dihydrate (3.0 equiv) dissolved in concentrated HCl.After 16 h the mixture was basified (pH 10) with 3 N NaOH and extractedwith CH₂Cl₂. The combined organic phase was washed with brine, driedover sodium sulfate and purified by column chromatography (gradientelution using 20% EtOAc-hexanes→50% EtOAc-hexanes) to afford 83% of thedesired product.

[0131] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 83% yield. HRMS calc for[C₃₉H₃₆ClN₃ O₅S+H] 694.2137 found 694.2136.

EXAMPLE 174-{2-[1-Benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0132] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) and dimethylsulfamoyl chloride according to theprocedure in Example 1 Step 7 in 49% yield.

[0133] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1to afford the title acid in 95% yield. HRMS calc for[C₃₄H₃₄ClN₃ O₅S+H] 632.1981 found 632.1984.

EXAMPLE 184-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-difluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0134] Step 1: To 3,4-difluorobenzyl bromide (1.0 equiv) in H₂O (0.74 M)was added sodium sulfite (1.1 equiv). The mixture was heated to refluxfor 16 hours then cooled to room temperature. The white precipitate wasfiltered and dried to afford 95% of the sodium sulfonate intermediate.

[0135] Step 2: To 3,4-difluorobenzyl sodium sulfonate (7.6 equiv) inCH₂Cl₂ (0.76 M) was added DMF (5.6 equiv) and SOCl₂ (30 equiv). After 1h the mixture was concentrated and azeotroped with toluene. The residuewas suspended in CH₂Cl₂ (0.38 M) and methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) (1.0 equiv) and sat. NaHCO₃ (0.76 M) were added.After 1 h the mixture was poured into H₂O and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography (gradient elution using 20%EtOAc-hexanes→40% EtOAc-hexanes) to afford 94% of the methyl esterintermediate.

[0136] Step 3: The methyl ester was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂ O₅S+H] 715.184 found 715.1843.

EXAMPLE 194-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0137] Step 1: The sulfonyl chloride intermediate was prepared from2-(bromomethyl)naphthalene according to the procedure in Example 18 Step1-2 in 34% yield.

[0138] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 58%yield.

[0139] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield. HRMS calc for[C₄₃H₃₇ClN₂ O₅S+H] 729.2185 found 729.2189.

EXAMPLE 203-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoicacid

[0140] Step 1: The sulfonyl chloride intermediate was prepared frommethyl 3-(bromomethyl)benzoate according to the procedure in Example 18Step 1-2.

[0141] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6 Example 1) according to the procedure in Example 1 Step 7 in 23%yield.

[0142] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 93% yield. HRMS calc for[C₄₀H₃₅ClN₂O₇S+H] 723.1926 found 723.1932

EXAMPLE 214-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)ethyl′1H-indol-3-yl}ethoxy)benzoicacid

[0143] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added trans-α-styrenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 66%yield.

[0144] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calc for[C₄₀H₃₅ClN₂ O₅S+H] 691.2028 found 691.2034.

EXAMPLE 224-{2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0145] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added trifluoromethylsulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 49%yield.

[0146] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₃H₂₈ClF₃N₂ O₅S+H] 657.1432 found 657.1435.

EXAMPLE 234-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0147] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added cyclopropanesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 75% yield.

[0148] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 84% yield. HRMS calc for[C₃₅H₃₃ClN₂ O₅S+H] 629.1872 found 629.1874.

EXAMPLE 244-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

[0149] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added 3,5-bis(trifluoromethyl)benzylsulfonylaccording to the procedure in Example 1 Step 7 to generate the productin 79% yield.

[0150] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. HRMS calc for[C₄₁H₃₃ClF₆N₂ O₅S+H] 815.1776 found 815.1776.

EXAMPLE 252-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoicacid

[0151] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added methyl (2-chlorosulfonyl)benzoate accordingto the procedure in Example 1 Step 7 to generate the product in 100%yield.

[0152] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 61% yield. HRMS calc for[C₃₉H₃₃ClN₂ O₇S+H] 709.177 found 709.1772.

EXAMPLE 264-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0153] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added 2-naphthalenesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 53% yield.

[0154] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₃₅ClN₂ O₅S+H] 715.2028 found 715.2034.

EXAMPLE 274-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0155] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added 3,5-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 60% yield.

[0156] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield. HRMS calc for[C₃₈H₃₁Cl₃N₂ O₅S+H] 733.1092 found 733.1096.

EXAMPLE 284-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0157] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added 3,4-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 60% yield.

[0158] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 80% yield. HRMS calc for[C₃₈H₃₁Cl₃N₂ O₅S+H] 733.1092 found 733.1094.

EXAMPLE 294-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1Hindol-3-yl]ethoxy}benzoic acid

[0159] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added (2,3-dichlorophenyl)-methyl]sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 50% yield.

[0160] Step2-The resulting ester was hydrolyzed by stirring with KOH (67mg, 5 equiv.) in THF (5 mL) MeOH (5 mL) and H₂O (2 mL). The reaction wasmonitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance of startingmaterial. The mixture was stirred overnight at room temperature and thenconcentrated, diluted with H₂O, and acidified to pH 2-4 using 1 M HCl.The aqueous phase was extracted with EtOAc and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated to affordthe desired product in 98% yield. HRMS calc for [C₃₉H₃₃Cl₃N₂O₅S+H]747.1249 found 747.1254.

[0161] EXAMPLE 30

4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0162] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added (2,4-dichlorophenyl)-methyl]sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 98% yield.

[0163] Step2- The ester intermediate was hydrolyzed according to Step 2Example 29 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂ O₅S+H] 747.1249 found 747.1255.

EXAMPLE 314-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1Hindol-3-yl]ethoxy}benzoic acid

[0164] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added (2-chlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 86% yield.

[0165] Step2- The ester intermediate was hydrolyzed according to Step 2Example 29 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂ O₅S+H] 713.1638 found 713.1644.

EXAMPLE 324-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0166] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added [(4-chloro-2-nitro)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 74% yield.

[0167] Step2- The ester intermediate was hydrolyzed according to Step 2Example 29 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₃Cl₂N₃ O₇S+H] 758.1489 found 758.1494.

[0168] The acid resulting from Method A, or any subsequent method couldbe used as a subtrate for palladium catalyzed amination reaction using abase, an amine, a phosphine ligand and palladium reagent.

EXAMPLE 334-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-′3-yl)ethoxy]benzoicacid

[0169] Step 1- A flask was charged with tris(dibenzylideneacetone)dipalladium(0) (0.01 eq.), 2-(di-t-butylphosphino)biphenyl (0.04 eq.),sodium t-butoxide (2.4 eq.) and the acid from step 8 (1.0 eq.). 1.5 mltoluene (1.0 M) was added to the flask followed by morpholine (1.2 eq.)The reaction was heated to reflux for five hours. The reaction mixturewas partitioned between 5% hydrochloric acid and dietheyl ether. Theorganic layer was washed with distilled water, followed by brine, driedover sodium sulfate and concentrated. The product was purified bypreparatory LC-MS to afford 7.8% of the desired product. HRMS calc for[C₄₃H₄₃N₃ O₆S+H] 730.2945 found 730.2945.

EXAMPLE 344-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0170] Step 1: (2-Cyano-phenyl)-methanesulfonyl chloride was preparedaccording to Example 18 Step 1-2 (crude yield 100%).

[0171] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7as a white solid in 72% yield.

[0172] Step3- The ester intermediate was hydrolyzed according to Step 8Example to afford the title acid in 74% yield. MS (ES) m/z (M−1) 702.0;HRMS Calcd. for C₄₀H₃₅ClN₃O₅S (M+1): 704.1980. Found: 704.1984. Anal.Calcd. for C₄₀H₃₄ClN₃O₅S: C, 68.22; H, 4.87; N, 5.97. Found: C, 67.92;H, 5.11; N, 5.54.

EXAMPLE 354-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-difluorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0173] Step 1: The sulfonyl chloride intermediate was prepared from3,5-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in 95% yield.

[0174] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 78%yield.

[0175] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 83% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂ O₅S+H] 715.184 found 715.1842.

EXAMPLE 364-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-cyanobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0176] Step 1: (3-Cyano-phenyl)-methanesulfonyl chloride was preparedaccording to Example 18 Step 1-2 (crude yield 100%).

[0177] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(3-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.

[0178] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. MS (ES) m/z (M−1)702.1; HRMS Calcd. for C₄₀H₃₃ClN₃O₅S (M−1):702.1834. Found: 702.1833.Anal. Calcd. for C₄₀H₃₄ClN₃O₅S.0.8H₂O: C, 67.00; H, 5.00; N, 5.86.Found: C, 67.22; H, 5.19; N, 5.44.

EXAMPLE 374-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl-)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0179] Step 1(4-Cyano-phenyl)-methanesulfonyl chloride was preparedaccording to Example 18 Step 1-2 (crude yield 100%).

[0180] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1)and(4-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.

[0181] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 77% yield.MS (ES) m/z (M−1) 702.1;HRMS Calcd. for C₄₀H₃₅ClN₃O₅S (M+1): 704.1980. Found: 704.1981. Anal.Calcd. for C₄₀H₃₄ClN₃O₅S: C, 68.22; H, 4.87; N, 5.97. Found: C, 68.09;H, 4.97; N, 5.73.

EXAMPLE 384-(2-{1-Benzhydryl-5-chloro-2-[2-({[4-(1piperidinyl-sulfonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0182] Step 1:[4-(Piperidine-1-sulfonyl)-phenyl]-methanesulfonylchloride was prepared according to Example 18 Step 1-2 (crude yield100%).

[0183] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and4-(Piperidine-1-sulfonyl)-phenyl]-methanesulfonyl according to Example 1Step 7.

[0184] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 73% yield. MS (ES) m/z (M−1)824.2; HRMS Calcd. for C₄₄H₄₃ClN₃O₇S₂ (M−1):824.2236. Found: 824.2246.Anal. Calcd. for C₄₄H₄₄ClN₃O₇S₂.0.5H₂O: C, 63.25; H, 5.43; N, 5.03.Found: C, 62.85; H, 5.64; N, 4.64.

EXAMPLE 394-(2-{2-[2-({[4-(Aminosulfonyl)benzyl]sulfonyl}-amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

[0185] Step 1: (4-Sulfamoyl-phenyl)-methanesulfonyl chloride wasprepared according to Example 18 Step 1-2 (crude yield 100%).

[0186] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(4-Sulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1Step 7.

[0187] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 69% yield. MS (ES) m/z (M−1)755.9; HRMS Calcd. for C₃₉H₃₅ClN₃O₇S₂ (M−1): 756.1613. Found: 756.1612.Anal. Calcd. for C₃₉H₃₆ClN₃O₇S₂: C, 61.77; H, 4.79; N, 5.54. Found: C,61.93; H, 5.12; N, 5.19.

EXAMPLE 404-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methanesulfonyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0188] Step 1: ((4-Methanesulfonyl-phenyl)-methanesulfonyl chloride wasprepared according to Example 18 Step 1-2 (crude yield 100%).

[0189] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1)((4-Methanesulfonyl-phenyl)-methanesulfonyl chloride according toExample 1 Step 7.

[0190] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 75% yield. MS (ES) m/z (M−1)755.0; HRMS Calcd. for C₄₀H₃₈ClN₂O₇S₂ (M+1): 757.1804. Found: 757.1804.Anal. Calcd. for C₄₀H₃₇ClN₂O₇S₂.H₂O: C, 61.96; H, 5.07; N, 3.61. Found:C, 61.82; H, 5.10; N, 3.48.

EXAMPLE 414(2-{1-Benzhydryl-5-chloro-2-[2-(4-diethylsulfamoyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0191] Step 1: (4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride wasprepared according to Example 18 Step 1-2 (crude yield 100%).

[0192] Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride according toExample 1 Step 7.

[0193] Step3- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 66% yield. MS (ES) m/z (M−1)812.1; HRMS Calcd. for C₄₃H₄₅ClN₃O₇S₂ (M+1): 814.2382. Found: 814.2385.Anal. Calcd. for C₄₃H₄₄ClN₃O₇S₂.0.3H₂O: C, 62.99; H, 5.48; N, 5.14.Found: C, 62.91; H, 5.67; N, 4.79.

EXAMPLE 424-{3-[1-Benzhydryl-5-chloro-2-(2-phenylmethane-sulfonylamino-ethyl)-1H-indol-3-yl]-propyl}-benzoicacid

[0194] Step 1: A mixture of methyl-4-iodobenzoate (5.3 g, 20.2 mmol),allyl alcohol (1.78 g, 30.3 mmol), NaHCO₃ (4.24 g, 50.5 mmol), Pd(OAc)₂(0.14 g, 0.60 mmol), (n-Bu)₄NBr (6.55 g, 20.2 mmol) and 4-A molecularSieves (4.1 g) in anhydrous DMF (69 mL) was stirred at room temperaturefor 4 days. The reaction mixture was filtered through celite and thefiltrate poured onto water and extracted with EtOAc. Organic layer waswashed with brine, dried (Na₂SO₄), and concentrated under vacuum. Flashchromatography (silica gel, 10-20% EtOAc-hexanes) gave 2.11 g (85% basedon the recovered starting material) of the desired4-(3-Oxo-propyl)-benzoic acid methyl ester as a clear oil.

[0195] Step 2: To a solution of 5-chloro-2-methylindole (0.86 g, 5.2mmol) and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol)in methylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol),followed by triethylsilane (1.81 g, 15.6 mmol). The reaction mixture wasstirred overnight, quenched with sat. NaHCO₃ solution (50 mL), and theorganic layer was washed with sat. NaHCO₃ solution, water, brine, anddried (Na₂SO₄). Solvent was removed under reduced pressure, and theresidue was purified by flash column chromatography with 10-20%EtOAc/hexanes to yield the desired product in 94% (1.67 g) yield.

[0196] Step 3: To a solution of the product from step 2 (1.66 g, 4.86mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83mmol) under N₂ atmosphere. The mixture was stirred for 1 h at roomtemperature, followed by the dropwise addition of benzhydryl bromide(1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirredovernight at room temperature. Water (500 mL) was added to reactionmixture, it was extracted with EtOAc, washed with brine, dried (Na₂SO₄),and concentrated under reduced pressure to a brown syrup, which waspurified by silica-gel chromatography using 10% EtOAc/hexanes as eluentto isolate 4 as a white solid in 59% (1.47 g) yield.

[0197] Step 4: The product from above (1.46 g, 2.87 mmol) was dissolvedin CCl₄ (14.5 mL), followed by the addition of NBS (1.02 g, 5.73 mmol)and benzoyl peroxide (2 mg). The reaction mixture was heated to refluxfor 1 h (until all the starting material disappeared). This mixture wascooled to room temperature, filtered and the solid was washed with CCl₄.The filtrate was evaporated to a brown residue, which was dissolved inacetone (40 mL) and water (4 mL), Ag₂CO₃ (1.75 g, 3.16 mmol) was thenadded to this solution and after being stirred overnight at roomtemperature, it was filtered through celite, the solvent was evaporatedunder reduced pressure, and water was added to the residue. It wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), and evaporatedto a syrup, which was purified by 10% EtOAc/hexanes to isolate the2-formyl indole (1.13 g) in 75% yield. Alternatively the dibromide fromthe reaction with NBS could be poured into DMSO (10-20% concentration byweight) and stirred for 30 minutes at room temperature. When thereaction was deemed complete it was poured into water and the resultingprecipitate was isolated by filtration, the cake was washed with waterand dried to yield an essentially quantitative yield.

[0198] Step 5: To a solution of the 2 formyl indole from above (0.52 g,1 mmol) in CH₃NO₂ (6.2 mL) was added NH₄OAC (0.077 g, 1 mmol), themixture was heated to reflux for 1 h, NH₄OAc (0.077 g, 1 mmol) was thenadded, heating at reflux was continued for an additional 1 h, NH₄Oac(0.077 g, 1 mmol) was added again and the heating continued for further1 h. The reaction mixture was allowed to attain room temperature, EtOAc(50 mL) was added, followed by the addition of 100 mL water. The aqueouslayer was extracted with EtOAc, and the combined organic layers werewashed with brine, dried (Na₂SO₄), and evaporated to a yellow foam,which was subjected to chromatographic purification using 10%EtOAc/hexanes as an eluent to yield 6 as a yellow foam in 68% yield(0.38 g).

[0199] Step 6: Zn(Hg) was made by adding HgCl₂ (3.4 g, 7.2 mmol) to amixture of Zn-dust (34.68 g, 530.35 mmol) and 5% HCl (38 mL) in a 100 mLbeaker, this mixture was stirred vigorously for 10 min. Aqueous phasewas decanted and added 38 mL of 5% HCl again and the mixture was stirredfor 10 min. Aqueous phase was decanted. This solid was added to thevinyl nitro compound 6 (15 g, 26.57 mmol) in THF (660 mL) and conc. HCl(64.5 mL). This mixture was stirred at room temperature for 1 h, then atreflux for 15 min. The reaction mixture was cooled to room temperatureand filtered through celite. Aq. NH₄OH solution (200 mL) was added tothe filtrate, stirred for 15 min and THF was removed under reducedpressure. The aqueous layer was extracted with CH₂Cl₂, combined organiclayer was washed with brine, dried (Na2SO4) and concentrated to a brownfoam, which was purified by column chromatography by eluting the columnwith CHCl₃ in the beginning to remove non-polar impurities then with 2%MeOH/CHCl₃ to isolate the desired amine in 46% yield (6.1 g)

[0200] Step 7: To the amine(1.0 equiv.) and sat. NaHCO₃ (0.14 M) inCH₂Cl₂ (0.07 M) was added □-toluenesulfonyl chloride (1.0 equiv.). After1 h the mixture was poured into saturated sodium bicarbonate andextracted with CH₂Cl₂. The combined organic phase was washed with brine,dried over sodium sulfate and purified by column chromatography toafford 84% of the desired product.

[0201] Step 8: The resulting ester was hydrolyzed by stirring with 1NNaOH (5 equiv.) in THF (0.07 M) and enough MeOH to produce a clearsolution. The reaction was monitored by TLC (10% MeOH—CH₂Cl₂) for thedisappearance of starting material. The mixture was stirred overnight atroom temperature and then. concentrated, diluted with H₂O, and acidifiedto pH 2-4 using 1 M HCl. The aqueous phase was extracted with EtOAc andthe organic phase was washed with brine, dried over sodium sulfate, andconcentrated to afford the desired product in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂ O₄S+H] 677.2235 found 677.224.

EXAMPLE 434-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0202] Step 1: This compound was prepared from the intermediate inExample 42 step 6 and (3,5-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 43 Step 7 which yielded 98% of thedesired product.

[0203] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S+H] 745.1456 found 745.1458.

EXAMPLE 444-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0204] Step 1: This compound was prepared from the intermediate inExample 42 step 6 and (3,4-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 43 Step 7 which yielded 96% of thedesired product.

[0205] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S+H] 745.1456 found 745.1458.

EXAMPLE 454-[2-(1-benzhydryl-5-chloro-2-(2-[(methylsulfonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0206] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added methanesulfonyl chloride according to theprocedure in Example 4 Step 1 to generate the product in 92% yield.

[0207] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₃H₃₁ClN₂O₅S+H] 603.1715 found 603.1717.

EXAMPLE 464-[2-(1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid

[0208] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added benzenesulfonyl chloride according to theprocedure in Example 4 Step 1 to generate the product in 90% yield.

[0209] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₃ClN₂O₅S+H] 665.1872 found 665.1869

EXAMPLE 474-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0210] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added {[3-(trifluoromethyl)phenyl]methyl}sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 74% yield.

[0211] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.1902 found 747.1904

EXAMPLE 482-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoicacid

[0212] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added 2-phthalimidoethanesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 78% yield.

[0213] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₄₂H₃₈ClN₃O₈S+H] 780.2141 found 780.2148

EXAMPLE 494-{2-[{1-benzhydryl-5-chloro-2-(2-{[(3-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0214] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added (3-pyridylmethyl)sulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 52%yield.

[0215] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₄ClN₃O₅S−H] 678.18349 found 678.18277.

EXAMPLE 504-{2-[{1-benzhydryl-5-chloro-2-(2-{[(4-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0216] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added (4-pyridylmethyl)sulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 57%yield.

[0217] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (−1) HRMS calc for[C₃₈H₃₄ClN₃O₅−H] 678.18349 found 678.18249

EXAMPLE 514-{2-[(1-benzhydryl-5-chloro-2-(2-{[(2-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0218] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1)was added (2-pyridylmethyl)sulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 42%yield.

[0219] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 56% yield. HRMS calc for[C₃₈H₃₄ClN₃O₅S−H] 678.18349 found 678.18312

EXAMPLE 524-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)-sulfonyl]amino}ethyl)-1H-indoly-3-yl]propyl}benzoicacid

[0220] Step 1: The sulfonyl chloride intermediate was prepared from2,6-dimethylbenzyl chloride according to the procedure in Example 18Step 1-2 in 100% yield.

[0221] Step 2: The methyl ester was prepared from the sulfonyl chlorideand the intermediate in Example 42 step 6 according to the procedure inExample 42 Step 7 in 30% yield.

[0222] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₄₁ClN₂O₄S−H] 703.24028 found 703.23973

EXAMPLE 534-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0223] Step 1: The sulfonyl chloride intermediate was prepared from(bromomethyl)cyclohexane according to the procedure in Example 18 Step1-2 in 100% yield.

[0224] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 20%yield.

[0225] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 73% yield. HRMS calc for[C₃₉H₄₁ClN₂O₅S−H] 683.23519 found 683.23474

EXAMPLE 544-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0226] Step 1: The sulfonyl chloride intermediate was prepared from4-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2in 95% yield.

[0227] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 80%yield.

[0228] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 90% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇S+H] 724.1879 found 724.1884.

EXAMPLE 554-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0229] Step 1: The sulfonyl chloride intermediate was prepared from3-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2in 95% yield.

[0230] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 85%yield.

[0231] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 85% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇S+H] 724.1879 found 724.1885.

EXAMPLE 564-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0232] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-nitro-□-toluenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0233] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆ClN₃O₆S+H] 722.2086 found 722.2088.

EXAMPLE 574-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0234] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and (4-Fluoro-phenyl)-methanesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 77% yield.

[0235] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 68% yield. HRMS calc for[C₄₀H₃₆ClFN₂O₄S+H] 695.2141 found 695.2145.

EXAMPLE 584-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

[0236] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and(4-Trifluoromethyl-phenyl)-methanesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 50% yield.

[0237] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₁H₃₆ClF₃N₂O₄S+H] 745.2109 found 745.2114.

EXAMPLE 594-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

[0238] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and(3-Trifluoromethyl-phenyl)-methanesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 56% yield.

[0239] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc for[C₄₁H₃₆ClF₃N₂O₄S+H] 745.2109 found 745.211.

EXAMPLE 604-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0240] Step 1: To the methyl methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and (4-chlorophenyl)-methanesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 74% yield.

[0241] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 79% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.1846 found 711.1847.

EXAMPLE 614-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0242] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-2-yl-methanesulfonyl chloridechloride according to the procedure in Example 4 Step 1 to generate theproduct in 75% yield.

[0243] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S+H] 678.2188 found 678.2187.

EXAMPLE 624-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0244] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-3-yl-methanesulfonyl chloridechloride according to the procedure in Example 4 Step 1 to generate theproduct in 75% yield.

[0245] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield.

EXAMPLE 634-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0246] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-4-yl-methanesulfonyl chloridechloride according to the procedure in Example 4 Step 1 to generate theproduct in 75% yield.

[0247] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 77% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S−H] 676.20423 found 676.20405

EXAMPLE 644-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0248] Step 1: The sulfonyl chloride intermediate was prepared from3-chlorobenzyl bromide according to the procedure in Example 18 Step1-2.

[0249] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in10% yield.

[0250] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S−H] 709.17000 found 709.16961

Example 654-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0251] Step 1: The sulfonyl chloride intermediate was prepared from3-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2.

[0252] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in43% yield.

[0253] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 88% yield. HRMS calc for[C₄₀H₃₆ClN₃O₆S−H] 720.19405 found 720.19398

EXAMPLE 664-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0254] Step 1: The sulfonyl chloride intermediate was prepared from3-chlorobenzyl bromide according to the procedure in Example 18 Step1-2.

[0255] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in27% yield.

[0256] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 93% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S−H] 709.17000 found 709.16963

EXAMPLE 674-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0257] Step 1: The sulfonyl chloride intermediate was prepared from2,5-dichlorobenzyl bromide according to the procedure in Example 18 Step1-2.

[0258] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in59% yield.

[0259] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S−H] 743.13103 found 743.13079

EXAMPLE 684-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0260] Step 1: The sulfonyl chloride intermediate was prepared from3-methoxybenzyl bromide according to the procedure in Example 18 Step1-2.

[0261] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in20% yield.

[0262] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₁H₃₉ClN₂O₅S−H] 705.21954 found 705.21909

EXAMPLE 694-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoicacid

[0263] Step 1: The intermediate from Step 1 Example 56 was treated withSnCl₂ according to the procedure in Step 1 Example 16 to yield the aminoester in 99% yield.

[0264] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₈ClN₃O₄S−H] 690.21988 found 690.21941

EXAMPLE 704-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0265] Step 1: The sulfonyl chloride intermediate was prepared from2-Methylbenzyl bromide according to the procedure in Example 18 Step 1-2in quantitative yield.

[0266] Step 2: The methyl ester was prepared from the sulfonyl chlorideand the intermediate in Example 42 step 6 according to the procedure inExample 42 Step 7 in 50% yield.

[0267] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 93% yield. HRMS calc for[C₄₁H₃₉ClN₂O₄S−H] 689.22463 found 689.22421

EXAMPLE 714-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-trifluorometoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0268] Step 1: The sulfonyl chloride intermediate was prepared from4-Trifluorometoxybenzyl bromide according to the procedure in Example 18Step 1-2 in quantitative yield.

[0269] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in48% yield.

[0270] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₆S−H] 761.17054 found 761.17031

EXAMPLE 724-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0271] Step 1: The sulfonyl chloride intermediate was prepared from2-Fluoro, 6-nitrobenzyl bromide according to the procedure in Example 18Step 1-2 in quantitative yield.

[0272] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 91%yield.

[0273] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 740.05

EXAMPLE 734-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0274] Step 1: The c chloride intermediate was prepared from3,5-dichlorobenzyl bromide according to the procedure in Example 18 Step1-2 in theoretical yield.

[0275] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in100% yield.

[0276] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. m/z (M−1) 747.2. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S−H] 745.11030 found 745.10954.

EXAMPLE 744-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0277] Step 1: The sulfonyl chloride intermediate was prepared from2,6-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in 95% yield.

[0278] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 86%yield.

[0279] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 71% yield. m/z (M−1)714. HRMS calcfor [C₃₉H₃₃ClF₂N₂O₅S−H] 713.16940 found 713.16906

EXAMPLE 754-(2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0280] Step 1: (6-chloro-3-pyridinyl)-methanol (1.0 eq.) was taken up indichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.)and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to thesolution and filtration followed by concentration of the filtrateafforded (6-chloro-3-bromomethyl) pyridine in 62% yield.

[0281] Step 2: The sulfonyl chloride intermediate was prepared from theproduct of Step 1 according to the procedure in Example 18 steps 1-2.

[0282] Step 3: The methyl ester was prepared from the sulfonyl chlorideand methy4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 78%yield

[0283] Step 4: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₈H₃₃Cl₂N₃O₅S−H] 712.1445 found 712.14420.

EXAMPLE 764-(2-(1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloro-2-[pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0284] Step 1: 5,6-dichloro-3-pyridinemethanol (1.0 eq.) was taken up indichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.)and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to thesolution and filtration followed by concentration of the filtrateafforded the 5,6-dichloro-3-bromomethylpyridine in 130% yield.

[0285] Step 2: The sulfonyl chloride intermediate was prepared from theproduct of Step 1 according to the procedure in Example 18 steps 1-2 in81% yield

[0286] Step 3: The methyl ester was prepared from the sulfonyl chlorideand methy4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 79%yield

[0287] Step 4: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 109% yield. HRMS calc for[C₃₈H₃₂Cl₃N₃O₅S−H] 746.10554 found 746.10549.

EXAMPLE 774-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0288] Step 1: The sulfonyl chloride intermediate was prepared from3-methoxybenzyl bromide according to the procedure in Example 18 Step1-2 in 68% yield.

[0289] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 68%yield.

[0290] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 93% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+Na] 731.1953 found 731.1947.

EXAMPLE 784-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0291] Step 1: The sulfonyl chloride intermediate was prepared from3,5-dimethylbenzyl bromide according to the procedure in Example 18 Step1-2 in 38% yield.

[0292] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 38%yield.

[0293] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 88% yield. m/z (M−1)705.0 HRMScalc for [C₄₁H₃₉ClN₂O₅S−H] 705.21954 found 705.21916.

EXAMPLE 794-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0294] Step 1: The sulfonyl chloride intermediate was prepared from2-methylbenzyl bromide according to the procedure in Example 18 Step 1-2in 35% yield.

[0295] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 35%yield.

[0296] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 90% yield. m/z (M−1)691.0. HRMScalc for [C₄₀₁H₃₇ClN₂O₅S−H] 691.20389 found 691.20350

EXAMPLE 804-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0297] Step 1: The sulfonyl chloride intermediate was prepared from2,6-dichlorobenzyl bromide according to the procedure in Example 18 Step1-2 in 3% yield.

[0298] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7 in 3%yield.

[0299] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 92% yield. m/z (M−1)745.0

[0300] The intermediate amine, synthesized using method A, was treatedwith chloromethylsulfonyl chloride either under Schott and Baummanconditions or under anhydrous conditions with an organic base yielded achloromethyl sulfonamide intermediate. This intermediate could betreated with a variety of nucleophiles in DMF with a suitable organicbase, Hunigs base, triethylamine etc, and heated until the reaction wascomplete. The resulting intermediates where then hydrolyzed to yield thefinal compound. The following examples were synthesized with method C:Examples 81-86 and 118-121.

EXAMPLE 814-(2-{1-benzhydryl-5-chloro-[2({[(phenylsulfanyl)-methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0301] The title compound was synthesized as depicted in Method C.

[0302] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) was added chloromethanesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 99% yield.

[0303] Step 2: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate(0.080M, 1.0 equiv.) and iPr₂NEt (3.4 equiv.) in N,N-dimethylformamidewas added thiophenol (2.1-2.5 equiv.) and the mixture was stirred at 120oC for 3.5 days. The reaction mixture was diluted with EtOAc and washedwith water and brine. The combined organic phase was dried overmagnesium sulfate and purified by flash chromatography.

[0304] Step 3:The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. m/z (M−1) 709.11. HRMScalc for [C₃₉H₃₅ClN₂O₅S₂−H] 709.16031 found 709.15999.

EXAMPLE 82 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dimethyl-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0305] Step1:To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 2,6-dimethylthiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography with 25% EtOAc/hexane in 32% yield.

[0306] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 80% yield. m/z (M−1)751.0. HRMScalc for [C₄₁H₃₉ClN₂O₅S₂−H] 737.19161 found 737.19128.

EXAMPLE 834-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxy-phenyl-sulfanylmethanesulfonylamino)-ethyl]]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0307] Step 1:To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 2-methoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 30% EtOAc/hexane in 36% yield.

[0308] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 94% yield. m/z (M−1) 753.3. HRMScalc for [C₄₀H₃₇ClN₂O₆S₂−H] 739.17088 found 739.17052.

EXAMPLE 84 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-6-methyl-phenylsulfanylmethanesulfonylamino)-ethyl]]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0309] Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 2-chloro-6-methylthiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 25% EtOAc/hexane in 46% yield..

[0310] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. m/z (M−1)771.2. HRMScalc for [C₄₀H₃₆Cl₂N₂O₅S₂−H] 757.13699 found 757.13730.

EXAMPLE 85 4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0311] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 3,5-dichlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 25% EtOAc/hexane in 40% yield.

[0312] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1)793.2. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S₂−H] 777.08237 found 777.08159.

EXAMPLE 864-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0313] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)-sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 3,4-dimethoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography with 35% EtOAc/hexane in 40% yield..

[0314] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid compound in 99% yield. m/z(M−1)783.3. HRMS calc for [C₄₁H₃₉ClN₂O₇S₂−H] 769.18144 found 769.18120.

[0315] The intermediate amine, synthesized using method A, was treatedwith chloroethanesulfonyl chloride under anhydrous conditions with anorganic base yielded a vinyl sulfonamide intermediate. This intermediatecould be treated with a variety of nucleophiles in DMF with a suitableorganic base, Hunigs base, triethylamine etc, and heated until thereaction was complete. The resulting intermediates were then hydrolyzedto yield the final compound.

[0316] The following examples were synthesized with Method D: Examples87-99 and 100-105, 113-117, 122-125 and 139.

EXAMPLE 87 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin4-ylethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0317] The title compound was synthesis as depicted in Method D

[0318] Step 1:To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(0.16M, 1.0 equiv.), Step6, Example 1, and triethylamine (2.3 equiv.) inTHF was added 2-chloroethanesulfonyl chloride (1.2 eq) dropwise. After 4h the mixture was poured into brine and extracted with EtOAc. Thecombined organic phase was dried over magnesium sulfate and purified bycolumn chromatography to afford 75% of the vinyl sulfonamide.

[0319] Step2: To the product from step 1 in 1-propanol was addedmorpholine. After 5 h the reaction mixture was evaporated to drynessbefore redissolving in EtOAc. The organic phase was washed with brine,dried over magnesium sulfate, and purified by column chromatography togive the desired methyl ester in 89% yield.

[0320] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. m/z (M−1) 702.17. HRMScalc for [C₃₈H₄₀ClN₃O₆S−H] 700.2535 found 700.22500.

EXAMPLE 884-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0321] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 1H-pyrazole according to the procedure in Example87 step 2 except that it was heated at 80° C. for 18 h, in 90% yield.

[0322] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 61% yield. m/z (M−1) 681.24. HRMScalc for [C₃₇H₃₅ClN₄O₅S−H] 681.19439 found 681.19407.

EXAMPLE 89 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-phenylamino-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0323] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and aniline according to the procedure in Example 87step 2 except that it was heated at 80° C. for 8 days, in 50% yield.

[0324] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. m/z (M−1) 706.26. HRMScalc for [C₄₀H₃₈ClN₃O₅S−H] 706.21479 found 706.21452.

EXAMPLE 904-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0325] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 1,4-dioxa-8-aza-spiro[4.5]decane according to theprocedure in Example 87 step 2 except that it was stirred overnight, in82% yield.

[0326] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 756.2. HRMScalc for [C₄₁H₄₄ClN₃O₇S−H] 756.25157 found 756.25142.

EXAMPLE 914-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0327] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 1-Pyridin-2-yl-piperazine according to theprocedure in Example 87 step 2 except that it was stirred overnight, in86% yield.

[0328] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 776.2. HRMScalc for [C₄₃H₄₄ClN₅O₅S−H] 776.26789 found 776.26750.

EXAMPLE 924-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0329] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 1H-[1,2,4]triazole according to the procedure inExample 87 step 2 except that it was refluxed for 4 days, in 64% yield

[0330] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 682.1. HRMScalc for [C₃₆H₃₄ClN₅O₅S−H] 682.18964 found 682.18964.

EXAMPLE 934-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0331] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 3,5-dimethyl-1H-pyrazole according to theprocedure in Example 87 step 2 except that it was refluxed for refluxed24 hours, in 95% yield.

[0332] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 62% yield. m/z (M−1) 709.2. HRMScalc for [C₃₉H₃₉ClN₄O₅S−H] 709.22569 found 709.22532.

EXAMPLE 944-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0333] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 3-methyl-1H-pyrazole according to the procedure inExample 87 step 2 except that it was stirred overnight, in 88% yield.

[0334] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 86% yield. m/z (M−1) 695.2. HRMS calc for [C₃₈H₃₇ClN₄O₅S−H]695.21004 found 695.20951.

EXAMPLE 954-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0335] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 4-methyl-1H-pyrazole according to the procedure inExample 87 step 2 except that it was refluxed for 2 days, in 81% yield.

[0336] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 93% yield. m/z (M−1) 695.2. HRMS calc for [C₃₈H₃₇ClN₄O₅S−H]695.21004 found 695.20954

EXAMPLE 964-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0337] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 2,6-dimethyl-piperidine according to the procedurein Example 87 step 2 except that it was heated at 70° C. overnight, in54% yield.

[0338] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 79% yield. m/z (M−1) 726.3. HRMS calc for [C₄₁H₄₆ClN₃O₅S−H]726.27739 found 726.27720.

EXAMPLE 974-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0339] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and imidazolidine-2-thione according to the procedurein Example 87 step 2 except that it was refluxed for 3 days, in 17%yield..

[0340] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 88% yield. m/z (M−1) 715.3. HRMS calc for [C₃₇H₃₇ClN₄O₅S−H]715.18211 found 715.18161.

EXAMPLE 984-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0341] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and thiazolidine according to the procedure in Example87 step 2 except that it was refluxed overnight, in 33% yield.

[0342] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 93% yield. m/z (M−1) 702.3. HRMS calc for [C₃₇H₃₈ClN₃O₅S₂−H]702.18686 found 702.18659.

EXAMPLE 994-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

[0343] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 1H-[1,2,3]triazole according to the procedure inExample 87 step 2 except that it was refluxed for 5 days, in 23% yield.

[0344] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 100% yield. m/z (M−1) 682.0. HRMS calc for [C₃₆H₃₄ClN₅O₅S−H]682.18964 found 682.18933.

EXAMPLE 100 4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid

[0345] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate,Step 6, Example 42, (0.16M, 1.0 equiv.) and triethylamine (2.3 equiv.)in THF was added 2-chloroethanesulfonyl chloride (1.2 eq) dropwise.After 4 h the mixture was poured into brine and extracted with EtOAc.The combined organic phase was dried over magnesium sulfate and purifiedby column chromatography to afford the vinyl sulfonamide.

[0346] Step2: To the product from step 1 in 1-propanol was addedmorpholine. After 5 h the reaction mixture was evaporated to drynessbefore redissolving in EtOAc. The organic phase was washed with brine,dried over magnesium sulfate, and purified by column chromatography togive the desired methyl ester in 100% yield.

[0347] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. m/z (M−1) 698.12. HRMScalc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found 698.24581.

EXAMPLE 1014-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(2,6-dimethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid

[0348] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 2,6-dimethylpiperdine according to the procedurein Example 100 step 2 except that it was refluxed for heated at 80° C.for 1 d 17 h, in 59% yield.

[0349] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. m/z (M−1) 724.20. HRMScalc for [C₄₂H₄₈ClN₃O₄S−H] 724.29813 found 724.29776.

EXAMPLE 1024-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-pyrazol-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid

[0350] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 3,5-dimethyl-1H-pyrazole according to theprocedure in Example 100 step 2 except that it was refluxed for heatedat 80° C. for 1 d, in quantitative yield.

[0351] Step2- The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. m/z (M−1) 707.16. HRMScalc for [C₄₀H₄₁ClN₄O₄S−H] 707.24642 found 707.24597.

EXAMPLE 103 and 1044-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid and4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0352] Step 1: The mixture of4-{2-[1-Benzhydryl-5-chloro-2-(2-ethenesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.2 M, 1.0 equiv.), 1H-tetrazole(4.0 equiv.) andiPr₂NEt(4.3 equiv.) in 1-propanol was refluxed overnight. It wasevaporated to dryness before redissolving in EtOAc. The organic phasewas washed with water and brine, dried over magnesium sulfate, purifiedby column chromatography to give two isomers in 41% and 52% yields,respectively.

[0353] Step2: The ester intermediates were hydrolyzed according to Step8 Example 1, except that the pH was adjusted to 4-5, to afford the titleacids4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 92% yield. m/z (M−1) 683.3;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 83% yield. m/z (M−1) 683.3. HRMS calc for [C₃₅H₃₃ClN₆O₅S−H]683.18489 found 683.18458;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 83% yield. HRMS calc for [C₃₅H₃₃ClN₆O₅S−H] 683.18489 found683.18435.

[0354] The substituted nitro aromatic was treated with ethyl oxalate inthe presence of potassium or sodium in an alcoholic solvent. Theresulting oxalate ester was treated with a suitable reducing agent, suchas iron powder, and the resulting amine cyclized to the indole under thereaction conditions. The carboxylate was next reduced with any of avariety of reducing agents, lithium aluminum hydride, dibal etc and theresulting alcohol was oxidized using reagents such as manganese dioxide,Swern condition NMO/TPAP etc. This 2 formyl indole was next alkylated bytreatment with a strong base such as Na/KHMDS, NaH, etc and thenalkylated with a suitable halide. The aldehyde was next treated withnitromethane and a base such as ammonium acetate to yield a vinyl nitrointermediate that could be reduced by a variety of agents such asLithium Aluminum Hydride or Zn(Hg) amalgam in HCl. The resulting aminewas sulfonylated using a sulfonyl chloride either under biphasic Schottand Baummen conditions or anhydrous conditions with an organic base.This intermediate could be reductively alkylated at C3 using an aldehydeor an acetal under the action of a Bronsted or Lewis acid such astrifluoroacetic acid and a reducing agent such as triethylsilane. Theresulting intermediate was hydrolyzed using a base, NaOH, KOH, LiOH anda mixture of solvents including an alcoholic solvent, water andtetrahydrofuran. The following Examples 105-107 were synthesized usingMethod E.

EXAMPLE 1054-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid

[0355] Step 1: To potassium (6.24 g) in ether at rt were added ethanol(40 mL, in 100 mL ether), diethyl oxalate (27.85 g, in 60 mL ether), and4-chloro-2-nitrotoluene (in 40 mL ether). The reaction mixture wasstirred at rt for 15 h and followed by sonication for 7 h before pouringonto cold 1N HCl. After neutralization, the aqueous layer was extractedwith EtOAc and the combined organic layers were washed with brine anddried. After evaporation, the crude3-(4-Chloro-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester was useddirectly in the next step without further purification.

[0356] Step 2: To crude 3-(4-chloro-2-nitro-phenyl)-2-oxo-propionic acidethyl ester (151 mmol) in ethanol:glacial HOAc (1:1, v/v, 560 mL) at rtwas added iron powder (74.4 g) and the reaction mixture was stirred atreflux for 4 h. The mixture was filtered and evaporated to give aresidue which was redistributed in dichloromethane/1N HCl. The organiclayer was washed with 1N HCl, NaHCO₃, and brine and dried. Evaporationfollowed by crystallization (DCM) gave 6-Chloro-1H-indole-2-carboxylicacid ethyl ester as a pale yellow solid (16.8 g, 50% over 2 steps).

[0357] Step 3: To 6-chloro-1H-indole-2-carboxylic acid ethyl ester (8.57g) in THF at 0° C. was added lithium aluminum hydride solution (1M, inTHF) dropwise and the reaction mixture was stirred for 3.5 h. Themixture was quenched with H₂O, 15% NaOH, and H₂O before it was filteredand rinsed with THF. Evaporation of the solvent gave 7.77 g of the crude(6-Chloro-1H-indol-2-yl)-methanol which was used directly in the nextstep.

[0358] Step 4: To (6-chloro-1H-indol-2-yl)-methanol (37.7 mmol) in THFat 0° C. was added manganese (IV) oxide and the mixture was stirred atrt for 16 h. The mixture was filtered over celite and rinsed with THFand EtOAc and evaporated to near dryness. The solid was filtered andwashed with cold EtOAc/hex to give 6-Chloro-1H-indole-2-carbaldehyde(62%, 2 steps).

[0359] Step 5: To 6-chloro-1H-indole-2-carbaldehyde (1 equiv.) in DMF at0° C. was added NaH (1.25 equiv.) portionwise followed by benzhydrylbromide (1.46 equiv.) and Bu₄Nl (0.05 equiv.). The mixture was stirredat rt for 42 h before quenching with cold 0.4N HCl at 0° C. Afterneutralization, the aqueous layer was extracted with ether and theorganic layer was washed with cold H₂O and dried. Flash chromatographyon silica gel gave 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde in 40%yield.

[0360] Step 6: A solution of1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde (0.5M, 1 equiv.) andNH₄OAc (1 equiv.) in nitromethane was heated at 95° C. for 70 min. Themixture was diluted with EtOAc, washed with water, and dried.Evaporation of the volatiles, followed by trituration with ether/hexaneproduced 1-Benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indole in 48% yield.

[0361] Step 7: To lithium aluminum hydride (1M in THF, 4 equiv.) in THFat 0° C. was added 1-benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indole(0.1M, 1 equiv.) dropwise and the reaction mixture was stirred for 2 h.The mixture was quenched with H₂O, 15% NaOH, and H₂O, filtered throughcelite and rinsed with EtOAc. After evaporation, the residue waspurified by column chromatography to generate2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine in 40% yield.

[0362] Step 8: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine wasadded phenylmethanesulfonyl chloride according to the procedure inExample 1 Step 7 to generateN-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamidein 90% yield.

[0363] Step 9: ToN-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamide(0.033M, 1 equiv.) in DCM at 0° C. were added 4-(2-oxo-ethoxy)-benzoicacid methyl ester (3.3 equiv.), triethylsilane (6 equiv.), and TFA (5equiv.). The reaction mixture was stirred at rt for 2 d 20 h beforeaqueous workup. Purification by silica gel chromatography followed byreverse phase HPLC gave4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester in 35% yield.

[0364] Step 10: The ester intermediate from step 9 was hydrolyzedaccording to Step 8 Example 1 to afford the title acid in 64% yield.

EXAMPLE 106 4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0365] Step 1: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine,Example 105 step 7 was added (3,4-dichloro-phenyl)-methanesulfonylchloride according to the procedure in Example 105 Step 7 to generateN-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidein quantitative yield.

[0366] Step 2:N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidewas reductively alkylated as described in Example 105 step 9 to give4-(2-{1-benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 38% yield.

[0367] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. m/z (M−1) 747.27.

EXAMPLE 107 4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0368] Step 1: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine,Example 105 step 7 was added (3,5-dichloro-phenyl)-methanesulfonylchloride according to the procedure in Example 105 Step 7 to generateN-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,5-dichloro-phenyl)-methanesulfonamidein quantitative yield.

[0369] Step 2:N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidewas reductively alkylated as described in Example 105 step 9 to give4-(2-{1-benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 31% yield.

[0370] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+Na] 769.1 found 769.1079..

EXAMPLE 1084-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0371] Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-benzonitrile according to the procedure in Example 18 Step1-2 in 100% yield.

[0372] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7.

[0373] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 72% overall yield. HRMS calcd. forC₄₀H₃₅ClN₃O₅S (M+1): 704.1980; found: 704.1984. HRMS calcd. forC₄₀H₃₅ClN₃O₅S (M+1): 704.1980; found: 704.1984.

EXAMPLE 1094-{2-[1-Benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0374] Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-tetrahydro-pyran according to the procedure in Example 18Step 1-2 in 100% yield.

[0375] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7.

[0376] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 20% overall yield HRMS calcd. forC₃₈H₃₈ClN₂O₆S (M−1): 685.2145; found: 685.2143.

EXAMPLE 1104-{2-[1-Benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

[0377] Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-benzooxazole according to the procedure in Example 18 Step1-2 in 100% yield.

[0378] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7.

[0379] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 26% overall yield. HRMS calcd. forC₄₀H₃₅ClN₃O₆S (M+1): 720.1930; found: 720.1924.

EXAMPLE 1114-{2-[1-Benzhydryl-5-chloro-2-(2-{[(cyanomethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0380] Step 1: The sulfonyl chloride intermediate was prepared from3-bromomethyl-[1,2,4]oxadiazole according to the procedure in Example 18Step 1-2 in 100% yield.

[0381] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7.

[0382] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 59% overall yield. HRMS calcd. forC₃₄H₃₁ClN₃O₅S (M+1): 628.1668; found: 628.1662.

EXAMPLE 1124-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0383] Step 1: The sulfonyl chloride intermediate was prepared from3-bromomethyl 3-bromomethyl-thiophene according to the procedure inExample 18 Step 1-2 in 100% yield.

[0384] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step6, Example 1) according to the procedure in Example 1 Step 7.

[0385] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 25% overall yield. HRMS calcd. forC₃₂H₃₁ClN₂O₅S₂ (M−1): 683.1447; found: 683.1445.

EXAMPLE 1134-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0386] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 2-methyl-pyrrolidine according to the procedure inExample 87 step 2 in 91% yield.

[0387] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 99% yield. HRMS calc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found698.24572.

EXAMPLE 1144-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0388] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 2-methyl-piperidine according to the procedure inExample 87 step 2 in 91% yield.

[0389] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 96% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S−H] 712.26174 found712.26113.

EXAMPLE 1154-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2,5-dimethyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0390] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 2,5-dimethyl-pyrrolidine according to theprocedure in Example 87 step 2 in 81% yield.

[0391] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 96% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S−H] 712.26174 found712.26114.

EXAMPLE 1164-(2-{1-Benzhydryl-5-chloro-2-[2-(2-thiomorpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0392] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and thiomorpholine according to the procedure inExample 87 step 2 in 93% yield.

[0393] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 90% yield. HRMS calc for [C₃₈H₄₀ClN₃O₅S₂−H] 716.20251 found716.20217.

EXAMPLE 117 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-piperidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0394] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and piperidine according to the procedure in Example87 step 2 in 99% yield.

[0395] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 92% yield. HRMS calc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found698.24570.

EXAMPLE 118 4-{2-[1-benzhydryl-5-chloro-2-(2-o-tolylsulfanylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid

[0396] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added o-thiocresol according to the procedure inExample 81 step 2 and 3. The product was purified by the preparativeHPLC in 45% yield.

[0397] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1)723.07. HRMScalc for [C₄₀H₃₇ClN₂O₅S−H] 723.17596 found 723.17596.

EXAMPLE 119 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0398] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 2-chlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by thepreparative HPLC in 53% yield.

[0399] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. m/z (M−1)743.08. HRMScalc for [C₃₉H₃₄Cl₂N₂O₅S₂−H] 743.12134 found 743.12111.

EXAMPLE 1204-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0400] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step1, was added 2,6-dichlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by thepreparative HPLC in 15.7% yield and hydrolized acid in 37%.

[0401] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1) 776.93. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S₂−H] 777.08237 found 777.08205.

EXAMPLE 1214-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

[0402] Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2,5-dimethoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 35% EtOAc/hexane in 65% yield.

[0403] Step2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 99.5% yield. m/z (M−1)769.18 HRMScalc for [C₄₁H₃₉ClN₂O₇S₂−H] 769.18144 found 769.18121.

EXAMPLE 1224-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3-hydroxy-pyrrolidine-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0404] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 3-pyrrolidinol according to the procedure inExample 87 step 2 in 90% yield without the column purification.

[0405] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 84% yield. m/z (M−1)699.99. HRMS calc for [C₃₈H₄₀ClN₃O₆S−H]700.22535 found 700.22490.

EXAMPLE 1234-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(4-hydroxy-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0406] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and 4-hydroxypiperidine according to the procedure inExample 87 step 2 in 95% yield without the column purification.

[0407] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 42% yield. m/z (M−1)714.03. HRMS calc for [C₃₉H₄₂ClN₃O₆S−H]714.24100 found 714.24085.

EXAMPLE 1244-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0408] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and N-(2-piperidylmethyl)-dimethylamine according tothe procedure in Example 87 step 2 in 90% yield without the columnpurification.

[0409] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 71% yield. m/z (M−1)754.94. HRMS calc for [C₄₂H₄₉ClN₄O₅S−H]755.30394 found 755.30344

EXAMPLE 1254-(2-{1-Benzhydryl-5-chloro-2-[2-(2-imidazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0410] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and imidazoleaccording to the procedure in Example 87step 2 except that it was heated at 120° C. for 4.5 days, in 87% yield.

[0411] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 60% yield. m/z (M−1)681.17. HRMS calc for [C₃₇H₃₅ClN₄O₅S−H]681.19439 found 681.19409.

EXAMPLE 1264-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0412] Step 1: The sulfonyl chloride intermediate was prepared from2,6-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in quantitative yield.

[0413] Step 2: The methyl ester was prepared from the sulfonyl chlorideand methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in53% yield.

[0414] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. m/z (M−1)711.2. HRMScalc for [C₄₀H₃₅ClF₂N₂O₄S−H] 711.19013 found 711.18965.

EXAMPLE 1274-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0415] Step 1: 2-methylindole was treated with the intermediate fromExample 42 step 1 and the procedure from Example 42 step 2 to yield thedesired product in 88%.

[0416] Step 2: The product from above was alkylated with benzhydrylbromide according to the proceure in Example 42 step 3 to yield theproduct in 65%.

[0417] Step 3: The product from above was oxidized using the conditionsoutlined in Example 42 step 4 to yield the desired 2-formyl indole in85% yield.

[0418] Step 4: The indole from above was subjected to the nitro aldolconditions outlined in Example 42 step6

[0419] Step 5: The vinyl nitro compound from above was reduced under theconditions outlined in Example 42 step 6 to yield the desired aminoindole in 39% yield.

[0420] Step 6: The amine from step 5 was treated with(3,4-dichlorophenyl)-methyl]sulfonyl chloride according to the procedurein Example 43 Step 7 which yielded 100% of the desired product.

[0421] Step 7: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 24% yield. HRMS calc for[C₄₀H₃₆ClN₂O₄S−H] 709.1700 found 709.16951.

EXAMPLE 1284-[3-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0422] Step 1: This compound was prepared from the intermediate inExample 127 step 5 □-toluenesulfonyl chloride according to the procedurein Example 43 Step 7 which yielded 83% of the desired product.

[0423] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 95% yield. HRMS calc for[C₄₀H₃₈N₂O₄S−H] 641.24795 found 641.24761.

[0424] The appropriately substituted halo amine is reacted withtrifluoroacetic anhydride to yield an intermediate that could be treatedwith a Pd^(ii) catalyst in the presence of a base such as triethlyamineand Cul and a suitable alkyne under heat yielded the desired indoleintermediate. The primary alcohol was protected as a silyl ether using asilyl chloride such as t-Butyldiphenyl silyl chloride and a base such asimidazole. The protected indole is then treated with oxallyl chloridefollowed by methanol which produced the desired oxalate ester whichcould be alkylated using a suitable base such as cesium carbonate inrefluxing acetonitrile and a halide. The oxallate could then be reducedvia the action of a suitable reducing agent such as borane. Theresulting primary alcohol was converted to a halide, using for exampleCBr₄ and a phosphine, which could then be a nucleophile such as athiophenol. The resulting thioether could be oxidized by a variety ofoxidizing agents including oxone and TPAP/NMO. The resulting sulfone canbe deprotected via the action of a flouride source such as TBAF, CsF orHF. The resulting alcohol could be converted to a halide or mesylate,for example using methane sulfonyl chloride and an organic base, whichcould then be displaced by sodium azide in DMF.The resulting alkyl azidecould be reduced under the action of triphenyl phosphine and wet THF.The amine could be sulfonylated by the action of a sulfonyl chlorideunder either biphasic Shcott and Baumman conditions, Aq. Bicarbonate anddichloromethane, or under anhydrous conditions consisting ofdichloromethane and an organic base such as Hunigs base. The reultingintermediate was hydrolyzed using a base, NaOH, KOH, LiOH and a mixtureof solvents including an alcoholic solvent, water and tetrahydrofuran.The following Examples 129-132 were synthesized using Method F.

EXAMPLE 1293-[4-({2-[1-Benzhydryl-5-chloro-2-(2-{[(2-chloro-benzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

[0425] Step 1: 2-Bromo-4-chloroaniline(1.0 eq) was dissolved in CH₂Cl₂(0.25M), then triethylamine and triflouroacetyl anhydride(1.1 eq each)were added. The resulting mixture was stirred at room temperature for 1hour. Solvent was then stripped-off from the reaction mixture, and theresidue was purified by flash chromatography with dichloromethane aseluent to give the described product in 97% yield. m/z(M−H)⁻300.0.

[0426] Step 2: N-(2-Bromo-4-chlorophenyl)-2,2,2-trifluoroacetamide(step1, 1.0 eq) was mixed with 3-butyn-1-ol(2.0 eq),dichlorobis(triphenylphosphine)palladium(II) (2.5% eq),triethylamine(3.0 eq), Cul(5% eq) in DMF(0.2M) in a sealed vessel underN₂ and heated to 120° C. for 4 hours. The reaction mixture was thendiluted with ethyl acetate, washed with brine and dried over Na₂SO₄.Furthermore, evaporate the solvent and the residue was purified by flashcolumn chromatography with 2% MeOH/CH₂Cl₂ to give the describedproduct(A) in 67% yield. m/z(M−H)⁻194.09

[0427] Step 3: 2-(5-Chloro-1H-indol-2-yl)ethanol(step 2, 1.0 eq) andimidazole(2.0 eq) were dissolved in DMF(0.3M) at room temperature withstirring before tert-butylchlorodiphenylsilane (1.2 eq) was added. Theresulting mixture was kept stirred overnight at room temperature beforeit was quenched with a saturated sodium bicarbonate aqueous solution andextracted with ethyl acetate. Organic phase was washed with water andbrine and dried over Na₂SO₄. Solvent was removed and residue waspurified with column with CH₂Cl₂ as eluent to give the desired productas brown gum in over 90% yield. m/z(M−H)⁻433.0

[0428] Step 4:2-({[tert-Butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole(step 3, 1.0eq) was dissolved in ether (0.4M) and the solution was cooled to 0° C.Oxalyl chloride (1.2 eq) was added to the above cold solution withvigorous stirring. The reaction mixture was kept stirred at 0° C. for 1hour before EtOH was added, followed by NEt₃. The resulting mixture wasthen diluted with more EtOH before it was poured into water. Extractwith EtOAc. Organic phase washed with brine, dried over Na₂SO₄,concentrated to give the desired product as yellowish solid in 70%yield. m/z(M−H)⁻533.0

[0429] Step 5: Ethyl[2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate(step4, 1 eq), Ph₂CHBr(1.5 eq) and Cs₂CO₃(1.5 eq) were mixed in dryacetonitrile (0.1 M). The mixture was refluxed with stirring for 2hours. The reaction mixture was cooled to room temperature, added waterand extracted with EtOAc. Organic phase was concentrated and the residuewas columned with CH₂Cl₂ as eluent to give the desired product as orangegum in 45% yield. m/z(M+H)⁺701.3

[0430] Step 6: Ethyl[1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate(step5, 1 eq) was dissolved in THF (0.1M), then BH₃.Me₂S (2M in THF)(2 eq)wasadded to it. The resulting mixture was refluxed with stirring overnightunder N₂. The reaction mixture was cooled to room temperature, thenquenched slowly with 1N NaOH. Followed by EtOAc extraction, brine wash.Striping-off the solvent to give the described product in 65% yield.m/z(M+H)⁺645.0

[0431] Step 7:2-[1-Benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethanol(Step 6, leq) was dissolved in CH₂Cl₂(0.08M), then1,3-bis(diphenylphosphino)-propane (DPPP, 0.75 eq) was added. Thesolution was cooled to 0° C. under N₂, then CBr₄ (1.25 eq) was addedwith stirring. The stirring was continued for 2 hours while the reactiontemperature was allowed to return to room temperature. The solvent wasstripped off, and the residue was purified by passing through a shortcolumn with CH₂Cl₂ as eluent to give the desired product in quantitativeyield. m/z(M+H)⁺708.0

[0432] Step 8:1-Benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole(Step7, 1 eq) was mixed with methyl-3-(4-mercaptolphenyl)propionate (1.5 eq)and K₂CO₃ (1.5 eq) in DMF(0.1M). The resulting mixture was stirred atroom temperature under N₂ for 2 hrs, then water was added, followedethyl acetate extraction, brine wash, and column purification (CH₂Cl₂ aseluent) to give 80% of the desired product as brownish gum.m/z(M+H)823.0

[0433] Step 9: Methyl3-[4-({2-[1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(Step 8, 1 eq) was dissolved in acetonitrile(0.1M), then molecular sieve(powder, 4 A,) and 4-methylmorphorline N-oxide(NMO)(4 eq) were addedunder N₂. After 5 min, n-Pr₄NRuO₄ (TPAP)(5% eq) was added to it. Theresulting mixture was heated to 40° C. with stirring and kept for 1.5hrs. Strip-off the solvent, residue was columned with CH₂Cl₂, then1%EtOAc/CH₂Cl₂ as eluent to give the desired product as white foam in44% yield. m/z(M+H)⁺855.1

[0434] Step 10: Methyl3-(4-{2-[1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}phenyl)propanoate(Step 9, 1 eq) was dissolved in THF(0.1M) and cooled to 0° C., followedby nBu₄NF (1M in THF) (1.2 eq). The resulting mixture was stirred at 0°C. for 5′, then warmed up to room temperature and stirred for 30′.Strip-off solvent. The residue was columned with EtOAc/CH₂Cl₂ (1:9 to1:4) as eluent to give the described intermediate as white foam in 90%yield. m/z(M+H)⁺616.20

[0435] Step 11: Methyl3-[4-{2-[1-benzhydryl-5-chloro-2-(hydroxyethyl)-1H-indol-3-yl]ethyl}-sulfonyl)phenyl]propanoate(step10, 1 eq) in dichloromethane(0.02M) was treated at 0° C. with MeSO₂Cl(2.0 eq) and Et₃N(2.5 eq) and stirred for 1 hour. The ice-bath wasremoved and the reaction mixture was stirred for another 1 hour at roomtemperature before it was diluted with CH₂Cl₂, washed with NaH₂PO₄,brineand dried over Na₂SO₄. Evaporate solvent to give the described productin quantitative yield. m/z(M+H)⁺695.0

[0436] Step 11: Methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(step11, 1.0 eq) was dissolved in DMF(0.03M) and treated with NaN₃ (3.0 eq).The resulting mixture was heated to 60° C. and stirred for 2 hours,then, was added water, extracted with ethyl acetate, washed with brineand dried with Na₂SO₄. Evaporation of solvent yields quantitatively thedescribed product. m/z (M+H)⁺641.1

[0437] Step 12: Methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step12, 1 eq) was dissolved in THF(0.1M), and treated withtriphenylphosphine(1.1 eq). The reaction mixture was kept stirred for 2days before the addition of water, then stirred overnight. Strip offsolvent, residue was columned with 4%MeOH:CH₂Cl₂ as eluent to give thedescribed product in 71% yield. m/z(M+H)⁺615.2

[0438] Step 13: Methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step12, 1 eq) and (3,4-dichlorobenzyl)sulfonyl chloride(1.1) were dissolvedin CH₂Cl₂ (0.1M) at room temperature, then aqueous Na₂CO₃ solution wasadded with stirring. The stirring was continued for 2 hours. Then,organic phase was separated, washed with brine, dried with Na₂SO₄.Evaporate the solvent, the residue was columned with CH₂Cl₂ to 2%MeOH:CH₂Cl₂ as eluent to give 85% yield of the described product as whitesolid. m/z(M−H)⁻834.9

[0439] Step 14: Methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step 13, 1.0 eq) was dissolved in THF:MeOH (1:1) (0.1M), then added 1NNaOH. The mixture was kept stirred overnight at room temperature. Thesolvent was stripped off and the residue was dissolved in water to forma basic solution, which was neutralized with diluted HCl solution toprecipitate the product. The solid was collected by filtration, washedwith water, rinsed with hexane, then dried to give the desired productin 86% yield. HRMS calc for [C₄₁H₃₇Cl₃N₂O₆S₂+H] 823.12314 found823.12292.

EXAMPLE 1303-(4-{[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoicacid

[0440] Step 1: The intermediate from example 129, step 12 was treatedwith □-toluenesulfonyl chloride according to the procedure in example129 step 13 to yield the desired compound in 94% yield.

[0441] Step 2: The intermediate from above was treated with NaOHaccording to the procedure described in example 129, step 14 to yieldthe desired acid in 92% HRMS calc for [C₄₁H₃₉ClN₂O₆S₂+H] 755.20109 found755.20201.

EXAMPLE 1313-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

[0442] Step 1: The intermediate from example 129, step 12 was treatedwith (2,6-Difluoro-phenyl)-methanesulfonyl chloride according to theprocedure in example 129 step 13 to yield the desired compound in 42%yield.

[0443] Step 2: The intermediate from above was treated with NaOHaccording to the procedure described in example 129, step 14 to yieldthe desired acid in 83%. HRMS calc for [C₄₁H₃₇ClF₂N₂O₆S₂+H] 791.18224found 791.18257.

EXAMPLE 1323-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

[0444] Step 1: The intermediate from example 129, step 12 was treatedwith (2-fluoro-phenyl)-methanesulfonyl chloride according to theprocedure in example 129 step 13 to yield the desired compound in 42%yield.

[0445] Step 2: The intermediate from above was treated with NaOHaccording to the procedure described in example 129, step 14 to yieldthe desired acid in 86% yield. HRMS calc for [C₄₁H₃₈ClFN₂O₆S₂+H]773.19166 found 773.19213.

[0446] An intermediate from Method F could be alkylated at the C3position with aldehydes or the corresponding acetals in the presence ofa Lewis or Bronsted acid, such as boron triflouride etherate ortrifluoroacetic acid. The indole nitrogen may then be alkylated bytreatment with a strong base such as sodium bis(trimethylsilyl)amide,n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF,DMSO or THF followed by exposure to the appropriate halide. Theresulting thioether could be oxidized by a variety of oxidizing agentsincluding oxone and TPAP/NMO. The resulting sulfone can be deprotectedvia the action of a flouride source such as TBAF, CsF or HF. Theresulting alcohol could be converted to a halide or mesylate, forexample using methane sulfonyl chloride and an organic base, which couldthen be displaced by sodium azide in DMF.The resulting alkyl azide couldbe reduced under the action of triphenyl phosphine and wet THF. Theamine could be sulfonylated by the action of a sulfonyl chloride undereither biphasic Shcott and Baumman conditions, Aq. Bicarbonate anddichloromethane, or under anhydrous conditions consisting ofdichloromethane and an organic base such as Hunigs base. The reultingintermediate was hydrolyzed using a base, NaOH, KOH, LiOH and a mixtureof solvents including an alcoholic solvent, water and tetrahydrofuran.The following Examples 133, 135-138 and 140-141 were synthesized byMethod G.

EXAMPLE 1333-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

[0447] Step 1: Ethyl 4-[(2-oxoethyl)sulfanyl]propanoate (example 129step 3, 4.2 eq) was added to a solution containing2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 eq), TFA(3 eq), and 1,2-dichloroethane (0.1M) at 0° C. under N₂. Then Et₃SiH (12eq) was added and the reaction was allowed to return to room temperatureand stirred overnight. Quenched reaction with NaHCO_(3(aq)) andextracted with EtOAc and washed with brine and dried over sodiumsulfate. Purified with silica gel column and 1:5 EtOAc/Hexane as eluent.Obtained ethyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)propanoate(yellow oil) in 79% yield.

[0448] Step 2: Ethyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)propanoate(1 eq) was added to a suspension of NaH (1.1 eq) in DMF (0.38M) at 0° C.under N₂. After 30 minutes Ph₂CHBr was added and the reaction was warmedto room temperature. After 2.5 hours the reaction was quenched withNH₄Cl_((aq)) and extracted with EtOAc/Et₂O mix and washed with water andbrine and dried over sodium sulfate. Purified with silica gel column and1:6 EtOAc/Hexane. Obtained ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(yellow gum) in 42% yield.

[0449] Step 3: NMO (4 eq) was added to a solution/suspension containingethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(1 eq), ACN (0.1M), and molecular sieves (1 g/mmole of propanoate) underN₂. After 10 minutes TPAP (0.05 eq) was added and the mixture was heatedto 40° C. After 2 hours the reaction was cooled and filtered and thefiltrate was collected. Purified with silica gel column and 1:4EtOAc/Hexane. Obtained ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(white solid) in 86% yield.

[0450] Step 4: Tetrabutylammonium fluoride (1M in THF) (1.2 eq) wasadded to a solution of ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq) and THF (0.1M) at 0° C. under N₂. Warmed reaction to roomtemperature and after 30 minutes quenched with NH₄Cl_((aq)). Extractedwith EtOAc and washed with brine and dried over sodium sulfate. Purifiedwith silica gel column and 1:9 EtOAc/CH₂Cl₂. Obtained ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(white solid) in 88% yield.

[0451] Step 5: CH₃SO₂Cl (2 eq) and Et₃N (2.5 eq) were added to asolution of ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq) in CH₂Cl₂ (0.02M) at 0° C. under N₂. After 1 hour the reactionwas warmed to room temperature. After an additional hour water was addedand extracted with CH₂Cl₂ and washed with brine and dried over sodiumsulfate. Removed solvent to obtain ethyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(white solid) in 98% yield.

[0452] Step 6: Ethyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together underN₂ and heated to 60° C. After 1 hour the reaction was cooled and waterwas added. Extracted with EtOAc/Et₂O mix and washed with water and brineand dried over sodium sulfate. Removed solvent to obtain ethyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-brown solid) in 96% yield.

[0453] Step 7: Ethyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), PPh₃ (polymer supported) (1.3 eq), and THF (0.1M) were placedtogether under N₂. After 3 days water (1 mL/1 mmole propanoate) wasadded and reaction was stirred overnight. Filtered and collectedfiltrate. Purified with silica gel column and 2% MeOH in CH₂Cl₂.Obtained ethyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-brown solid) in 65% yield.

[0454] Step 8: (2-chlorobenzyl)sulfonyl chloride (2.2 eq) was added to amixture of ethyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂), and Na₂CO₃ (2.5 eq).After 2 hours more (2-chlorobenzyl)sulfonyl chloride (1.1 eq) was added.After an additional 1.5 hours the organic layer was recovered and washedwith brine and dried over sodium sulfate. Purified with silica gelpreparatory plate and 2% MeOH in CH₂Cl₂. Obtained ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-yellow gum) in 75% yield.

[0455] Step 9: Ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid (light-brown solid) in 83% yield. HRMS calc for [C₃₉H₃₆ClN₃O₄S+H]789.16211 found 5 789.16311.

[0456] The suitably substituted indole-2-carboxylate could be reducedvia a suitable reducing agent such as lithium aluminum hydride, dibaletc and then the resulting alcohol could be oxidized to the 2-formylindole using MnO₂, under Swern oxidation conditions or other oxidants.The indole nitrogen may then be alkylated by treatment with a strongbase such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. The aldehyde was next treated withnitromethane and a base such as ammonium acetate to yield a vinyl nitrointermediate that could be reduced by a variety of agents such asLithium Aluminum Hydride or Zn(Hg) amalgam in HCl. The resulting aminewas sulfonylated using a sulfonyl chloride either under biphasic Schottand Baummen conditions or anhydrous conditions with an organic base.Treatment of the the resulting sulfonamide with a strong base such assodium bis(trimethylsilyl) amide, n-BuLi, sodium hydride or potassiumhydride in a solvent such as DMF, DMSO or THF followed by exposure to asilyl chloride such as t-butyldimethyl silyl chloride to generate theprotected sulfonamide. This material could be formylated at C3 usingstandard Vilsmeier conditions conditions of POCl₃/DMF. The thus formed3-formyl indole was reductively aminated using a suitable amine, areducing agent such as sodium triacetoxyborohydride and acid such asglacial acetic acid. The resulting intermediate was hydrolyzed using abase, NaOH, KOH, LiOH and a mixture of solvents including an alcoholicsolvent, water and tetrahydrofuran. Example 134 was synthesized byMethod H.

EXAMPLE 1344-({[(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoicacid

[0457] Step 1: 5-Chloro-1H-indole-2-carboxylic acid ethyl ester (1 eq.)was dissolved in THF (0.4M), flushed with a nitrogen atmosphere and thenthe mixture was cooled to 0° C. and LAH (3 eq of a 1M solution in THF)was slowly added. The reaction was allowed to warm slowly to roomtemperature and stirred until TLC analysis indicated completion. Aftercooling the flask to 0° C., NaOH (60 ml 3N solution) was slowly addedand the reaction stirred until two layers were obtained. The layers wereseparated, aqueous was extracted 2× ethyl acetate, the combined organicswere washed with brine and then dried over magnesium sulfate andconcentrated to yield the desired alcohol that was used crude for thenext step.

[0458] Step 2: The product (1 eq.) from above was dissolved in THF (0.5M) and treated with manganese dioxide (3 eq), and stirred for 1.5 hoursuntil TLC analysis indicated that reaction was complete. The reactionwas filtered through celite, dried over magnesium sulfate, andconcentrated to yield the desired crude aldehyde in 82% yield.

[0459] Step 3: To the indole from above (1.0 eq) in DMF (0.36 M) at 25°C. was added NaH (1.2 eq, 60% dispersion in oil), and the brown solutionwas stirred at 0 to −5° C. for 1 h and then bromodiphenylmethane wasadded (1.1 eq), and then the reaction mixture was stirred overnight. Itwas then quenched with water, diluted with ethyl acetate, washed withwater and brine, dried over sodium sulfate and purified by columnchromatography to yield 60% of the desired product.

[0460] Step 4: To the above aldehyde (1.0 equiv) in CH₃NO₂ (0.075 M) wasadded ammonium acetate (9 equiv) and the resulting mixture was heated toreflux overnight. The reaction mixture concentrated to a small volumeand then diluted with EtOAc and washed with brine. The aqueous phase wasextracted with EtOAc. The combined organic extracts were washed withbrine, dried over sodium sulfate and concentrated and purification bycolumn chromatography to the desired nitroolefin (51% yield).

[0461] Step 5: Zinc dust (20 equiv) was suspended in 5% aqueous HClsolution (8 M Zn/5% HCl). To this mixture was added HgCl₂ (0.28 equiv).The mixture was shaken for 10 min, the aqueous phase was decanted andreplaced with fresh 5% HCl, and again the mixture was shaken for 5 minand the aqueous phase was removed. The zinc-mercury amalgam thusgenerated was then added to a mixture of the nitroolefin (1.0 equiv) andconc. HCl (80 equiv) in THF (0.04 M nitroolefin/THF). The mixture wasmaintained at a gentle reflux for 1 h. The formation of product wasfollowed by TLC analysis. The mixture was cooled to room temperature andthe solids were removed by filtration through Celite. Conc. NH₄OH wasadded to the solution phase and the mixture was concentrated on therotary evaporator. The residue was dissolved in CH₂Cl₂ and conc. NH₄OH.The aqueous phase was extracted with CH₂Cl₂, and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated to yieldthe desired crude amine(100%) that was used in the next step withoutpurification.

[0462] Step 7: To the amine form above (1.0 equiv) and sat. NaHCO₃ (0.14M) in CH₂Cl₂ (0.07 M) was added □-toluenesulfonyl chloride (1.0 equiv).After 1 h the mixture was poured into saturated sodium bicarbonate andextracted with CH₂Cl₂. The combined organic phase was washed with brine,dried over sodium sulfate and purified by column chromatography(gradient elution using 10% EtOAc-hexanes→20% EtOAc-hexanes) to afford40% of the desired sulfonamide.

[0463] Step 8:The sulfonamide from above was dissolved in DMF (0.5 M)under nitrogen atmosphere, cooled to 0° C., treated with sodium hydride(1.05 eq of a 60 oil dipersion), stirred for 15 minutes to ensure aniongeneration, treated with t-butyldimethsilyl chloride (1.2 eq) and thenstirred for two hours at 0° C. at which time TLC analysis indicated thereaction was complete. The reaction was worked up by partitioningbetween ½ saturated ammonium chloride solution and ethyl acetate,extraction of the aqueous layers with ethyl acetate(2×), washingcombined organic layers with brine (1×), drying over magnesium sulfateand concentrating to yield quantitative crude yield of the desiredprotected sulfonamide.

[0464] Step 9: To DMF (˜1 ml) was added phosporous oxychloride (1.2 eq),these reagents were stirred for 10 minutes and then a solution of theindole (1 eq) from above in DMF (0.8 M) was added. The resulting redreaction mixture is stirred for 4 hours, diluted with water and then thepH was adjusted to 8 (total volume of aqueous added about ¾ of DMF addedinitially) and then the reaction was refluxed for 2 hours and finallycooled, extracted with dicloromethane, aqueous layer extracted withdichloromethane (2×), combined organic layers washed with brine (1×),dried over magnesium sulfate and concentrated to yield 75% of a crudealdehyde that was used without further purification.

[0465] Step 10: To the aldehyde from above (1 eq) in THF (1.2 M) wasadded 4-aminomethyl-benzoic acid methyl ester (1.2 eq), sodiumtriacetoxyborohydride (1.5 eq) and acetic acid (glacial, 1.5 eq). Thereaction was stirred overnight and then worked up by the addition ofsaturated sodium bicarbonate and ethyl acetate, the layers wereseparated, the aqueous layer extracted with dichloromethane (2×),combined organic layers washed with brine (1×), dried over magnesiumsulfate and concentrated and purified via chromatography to yield 37% ofthe desired product.

[0466] Step 11: The resulting ester was hydrolyzed by stirring with 1NNaOH (5 equiv) in THF (0.07 M) and enough MeOH to produce a clearsolution. The reaction was monitored by TLC (10% MeOH—CH₂Cl₂) for thedisappearance of starting material. The mixture was stirred at roomtemperature for 72 hours.. The mixture was concentrated, diluted withH₂O, and acidified to pH 5 using 1 M HCl. The aqueous phase wasextracted with EtOAc and the organic phase was washed with brine, driedover sodium sulfate, and concentrated to afford the desired product in83% yield. HRMS calc for [C₃₉H₃₆ClN₃O₄S−H] 676.20423 found 676.20397.

EXAMPLE 1354-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]-ethyl}-5-chloro-1H-indol-3yl)ethyl]sulfonyl}benzoicacid

[0467] Step 1: 2-(5-chloro-1H-indol-2-yl)ethanol (1 eq) was added to asolution (under N₂) containing tert-Butyldiphenylchlorosilane (1.2 eq),imidazole (2.5 eq), and DMF (1.8M). The reaction was stirred overnight.Quenched with NaHCO_(3(aq)) and extracted with a Et₂O/EtOAc mixture. Theorganic layer was washed with water and brine and dried over sodiumsulfate. Purified with silica gel column and 1:4 Hexane/CH₂Cl₂ aseluent. Obtained2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (yellowoil) in 98% yield.

[0468] Step 2: Methyl 4-[(2-oxoethyl)sulfanyl]benzoate (3.7 eq) wasadded to a solution containing2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 eq), TFA(3 eq), and 1,2-dichloroethane (0.1M) at 0° C. under N₂. Then Et₃SiH (12eq) was added and the reaction was allowed to return to room temperatureand stirred overnight. Quenched reaction with NaHCO_(3(aq)) andextracted with EtOAc and washed with brine and dried over sodiumsulfate. Purified with silica gel column and 1:5 EtOAc/Hexane as eluent.Obtained methyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate(yellow solid) in 79% yield.

[0469] Step 3: Methyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate(1 eq) was added to a suspension of NaH (1.1 eq) in DMF (0.37M) at 0° C.under N₂. After 30 minutes Ph₂CHBr (1.8 eq) was added and the reactionwas warmed to room temperature. After 3 hours the reaction was quenchedwith NH₄Cl_((aq)) and extracted with EtOAc/Et₂O mix and washed withwater and brine and dried over sodium sulfate. Purified with silica gelcolumn and 1:5 EtOAc/Hexane. Obtained methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate(yellow gum) in 65% yield.

[0470] Step 4: NMO (4 eq) was added to a solution/suspension containingmethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate(1 eq), ACN (0.1M), and molecular sieves (1 g/mmole of benzoate) underN₂. After 10 minutes TPAP (0.12 eq) was added and the mixture was heatedto 40° C. After 1.5 hours the reaction was cooled and filtered and thefiltrate was collected. Purified with silica gel column and 1:5EtOAc/Hexane. Obtained methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(white solid) in 71% yield.

[0471] Step 5: Tetrabutylammonium fluoride (1M in THF) (1.2 eq) wasadded to a solution of methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq) and THF (0.1M) at 0° C. under N₂. Warmed reaction to roomtemperature and after 1 hour quenched with NH₄Cl_((aq)). Extracted withEtOAc and washed with brine and dried over sodium sulfate. Purified withsilica gel column and 1:9 EtOAc/CH₂Cl₂. Obtained methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(white solid) in 86% yield.

[0472] Step 6: CH₃SO₂Cl (2 eq) and Et₃N (2.5 eq) were added to asolution of methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq) in CH₂Cl₂ (0.02M) at 0° C. under N₂. After 1 hour the reactionwas warmed to room temperature. After an additional hour water was addedand extracted with CH₂Cl₂ and washed with brine and dried over sodiumsulfate. Removed solvent to obtain methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate(light-yellow solid) in 99% yield.

[0473] Step 7: Methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate(1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together underN₂ and heated to 60° C. After 1 hour the reaction was cooled and waterwas added. Extracted with EtOAc/Et₂O mix and washed with water and brineand dried over sodium sulfate. Removed solvent to obtain methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(light-yellow solid) in 99% yield.

[0474] Step 8: Methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), PPh₃ (2 eq), and THF (0.1M) were placed together under N₂ andstirred overnight. Water (1 mL/1 mmole benzoate) was added and reactionwas again stirred overnight. The solution was concentrated and purifiedwith silica gel column and 3:1 EtOAc/Hexane followed by 5% MeOH inCH₂Cl₂. Obtained methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(light-yellow solid) in 99% yield.

[0475] Step 9: alpha-Toluene sulfonyl chloride (2 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂), and Na₂CO₃ (2.5 eq).After 2 hours the organic layer was recovered and washed with brine anddried over sodium sulfate. Purified with silica gel preparatory plateand 3% MeOH in CH₂Cl₂. Obtained methyl4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate(off-white solid) in 94% yield.

[0476] Step 10: Methyl4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate(1 eq), THF (0.1 M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoicacid (off-white solid) in 92% yield. HRMS calc for [C₃₉H₃₅ClN₂O₆S₂−H]725.15523 found 725.15437.

EXAMPLE 1364-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

[0477] Step 1: (2-chlorobenzyl)sulfonyl chloride (3.4 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours more (2-chlorobenzyl)sulfonylchloride (3.4 eq) was added. After an additional 1.5 hours the organiclayer was recovered and washed with brine and dried over sodium sulfate.Purified with silica gel preparatory plate and 3% MeOH in CH₂Cl₂.Obtained methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(orange gum) in 40% yield.

[0478] Step 2: Methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (red-orange solid) in 80% yield. HRMS calc for [C₃₉H₃₄Cl₂N₂O₆S₂+H]761.13081 found 761.13146.

EXAMPLE 1374-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

[0479] Step 1: (2,6-difluorobenzyl)sulfonyl chloride (3.4 eq) was addedto a mixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(off-white solid) in 87% yield.

[0480] Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white-yellow solid) in 96% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂O₆S₂−H] 761.13638 found 761.13565.

EXAMPLE 1384-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

[0481] Step 1: (2-fluorobenzyl)sulfonyl chloride (3.4 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(off-white solid) in 82% yield.

[0482] Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (off-white solid) in 99% yield. HRMS calc for [C₃₉H₃₄ClFN₂O₆S₂−H]743.1458 found 743.14511.

EXAMPLE 1394-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0483] Step 1: The compound was prepared from the intermediate fromExample 87 step 1 and pyrrolidine according to the procedure in Example87 step 2 in 92% yield without the column purification.

[0484] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 92% yield. HRMS calc for [C₃₈H₄₀ClN₃O₅S−H] 684.23044 found684.23009.

EXAMPLE 140 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

[0485] Step 1: (3,4-dichlorobenzyl)sulfonyl chloride (2.1 eq) was addedto a mixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 1 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(white solid) in 87% yield.

[0486] Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white-yellow solid) in 93% yield. HRMS calc for[C₃₈H₃₃Cl₃N₂O₆S₂−H] 793.07728 found 793.07629

EXAMPLE 1414-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

[0487] Step 1: (2,6-methylbenzyl)sulfonyl chloride (3.0 eq, example 52,step 1) was added to a mixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(light-brown solid) in 81% yield.

[0488] Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white solid) in 99% yield. HRMS calc for [C₄₁H₃₉ClN₂O₆S₂+H]753.18653 found 753.18597.

[0489] Method J provides an alternative reaction scheme to a subset ofthe compounds contained in this document. A suitably substituted anilineis halogenated using ICl, I₂, or Br₂ and then the amine is protected asa carbamate, using for example triethylamine and a chloroformate. Thisaryl halide is coupled to a suitably functionalized alkyne under thereaction of Pd and copper catalysis in the presence of a base such astriethylamine. This resulting product could be cyclized using Pdcatalysis in the presence of allyl chloride and a substituted oxirane.The indole nitrogen may then be alkylated by treatment with a strongbase such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. The allyl indole could then betreated with 9-BBN and then a palladium catalyst followed by an aryl orvinyl iodide to effect a Suzuki coupling reaction. The resultingintermediate could be deprotected using a hydrazine or an alkyl amine toyield the primary amine. This amine could then be treated with therequisite sulfonyl chloride under biphasic conditions, aqueous sodiumbicarbonate/dichloromethane, or in organic solvent with the addition ofa hindered organic amine base. The final hydrolysis was accomplishedunder basic conditions with sodium hydroxide in water and methanol andTHF at room temperature or at elevated temperature. Alternatively it maybe cleaved by treatment with sodium thiomethoxide in a solvent such asTHF or DMF at elevated temperatures (50° C.-100° C.).

[0490] Method K provides an alternative method to prepare compounds ofthis invention. A suitably substituted aniline is halogenated using ICl,I₂, or Br₂ and then the amine is protected as a carbamate or amide,usingfor example trifluoroacetic anhydride triethyamine and dimethylaminopyridine. This intermediate is then reacted with a suitablyfunctionalized alkyne under palladium and copper catalysis in thepresence of a base. The resulting aryl alkyne is cyclized to the indoleby heating with an amine such as piperidine. Standard Mitsunobu reactionconditions, a phosphine, an azodicarboxylate and phthalamide are used togenerate the protected amine. The indole may be alkylated at the C3position (the indole 3-position carbon atom) with aldehydes or thecorresponding acetals in the presence of a Lewis or Bronsted acid, suchas boron triflouride etherate or trifluoroacetic acid. The indolenitrogen may then be alkylated by treatment with a strong base such assodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassiumhydride in a solvent such as DMF, DMSO or THF followed by exposure tothe appropriate halide. The resulting intermediate could be deprotectedusing a hydrazine or an alkyl amine to yield the primary amine. Thisamine could then be treated with the requisite sulfonyl chloride underbiphasic conditions, aqueous sodium bicarbonate/dichloromethane, or inorganic solvent with the addition of a hindered organic amine base. Thefinal hydrolysis was accomplished under basic conditions with sodiumhydroxide in water and methanol and THF at room temperature or atelevated temperature. Alternatively it may be cleaved by treatment withsodium thiomethoxide in a solvent such as THF or DMF at elevatedtemperatures (50° C.-100° C.).

[0491] Method L provides another alternative method to prepare compoundsof this invention. A suitably substituted halo aniline, see methods Jand K, and a symmetric alkynol or a monoprotected alkynol, for exampleTHP protection, are reacted in the presence of a base, copper andpalladium catalysis, followed by deprotection under acidic conditions ifa monoprotected substrate is used yielded the symmetrical indole diol.The diol is desymmetrized by treatment with carbonyl diimidazole in asuitable solvent and then the primary alcohol was substituted understandard Mitsunobu conditions, a phosphine, an azodicarboxylate and analcohol were used to generated the desired ether. The carbamate could beopened up by reaction with sodium azide to yield the alkyl azide. Theindole nitrogen may then be alkylated by treatment with a strong basesuch as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. Treatment with triphenyl phosphinein wet THf delivered the desired alkyl amine. This amine could then betreated with the requisite sulfonyl chloride under biphasic conditions,aqueous sodium bicarbonate/dichloromethane, or in organic solvent withthe addition of a hindered organic amine base. The final hydrolysis wasaccomplished under basic conditions with sodium hydroxide in water andmethanol and THF at room temperature or at elevated temperature.Alternatively it may be cleaved by treatment with sodium thiomethoxidein a solvent such as THF or DMF at elevated temperatures (50° C.-100°C.).

[0492] Method M provides a further strategy to furnish compounds of thisinvention. A suitably substituted aniline is halogenated using ICl, I₂,or Br₂ and then the amine can be alkylated using an organic base and ahalide. The thus formed alkyl amine is then reacted under palladiumcatalyzed conditions in the presence of a chloride source a base andwith or without a phsophine and the requisite alkyne to yield theindole. When the Z in the alkyne is NHSO₂(CH₂)_(n2)X1R1 the synthesis isfinished by hydrolysis under basic conditions with sodium hydroxide inwater and methanol and THF at room temperature or at elevatedtemperature. Alternatively it may be cleaved by treatment with sodiumthiomethoxide in a solvent such as THF or DMF at elevated temperatures(50° C.-100° C.).

[0493] When Z=NH₂

[0494] The resulting indole can then be treated with the requisitesulfonyl chloride under biphasic conditions, aqueous sodiumbicarbonate/dichloromethane, or in organic solvent with the addition ofa hindered organic amine base. The final hydrolysis was accomplishedunder basic conditions with sodium hydroxide in water and methanol andTHF at room temperature or at elevated temperature. Alternatively it maybe cleaved by treatment with sodium thiomethoxide in a solvent such asTHF or DMF at elevated temperatures (50° C.-100° C.).

[0495] When Z=OH

[0496] The resulting alcohol could be converted to a halide or mesylate,for example using methane sulfonyl chloride and an organic base, whichcould then be displaced by sodium azide in DMF. The resulting alkylazide could be reduced under the action of triphenyl phosphine and wetTHF. The amine could be sulfonylated by the action of a sulfonylchloride under either biphasic Shcott and Baumman conditions, Aq.Bicarbonate and dichloromethane, or under anhydrous conditionsconsisting of dichloromethane and an organic base such as Hunigs base.The resulting intermediate was hydrolyzed using a base, NaOH, KOH, LiOHand a mixture of solvents including an alcoholic solvent, water andtetrahydrofuran.

[0497] Method N provides a further strategy to furnish a subset of thecompounds of this invention. The C3 functionalized-2-formyl indole (Seemethod A) was reacted under Wittig, or other organometallic conditions,to generate an alkeneoate ester. This ester could be converted to theacid by treatment with Pd and the resulting unsaturated acid was reducedvia hydrogenation. The alkyl acid was activated by conversion to theacid chloride, under the action of oxalyl chloride, or the acidflouride, via cyanuric flouride, and then treated with a suitableborohydride reducing agent to generate the alcohol. The alcohol wasconverted to the bromide using triphenyl phosphine andcarbontetrabromide and then displaced by the anion of the sulfonamide,generated by treating the primary sulfonamide with a strong base, suchas NaH, n-BuLi etc, to yield the desired secondary sulfonamide. Theresulting ester intermediate was hydrolyzed using a base, NaOH, KOH,LiOH and a mixture of solvents including an alcoholic solvent, water andtetrahydrofuran.

EXAMPLE 1424-[2-(1-benzhydryl-2-{3-[(benzylsulfonyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0498] Step 1: 5.0 g of4-[2-(1-Benzhydryl-2-formyl-1H-indol-3-yl)-ethoxy]-benzoic acid methylester, Step 4, Example 1, (0.0092M, 1.0 eq.) and 5.0 g ofallyl(triphenylphosphoranylidene) acetate (0.0139M, 1.5 eq.) weredissolved in 250 mL of tetrahydrofuran at room temperature. The paleyellow solution was stirred for one hour. TLC indicated a new spot at□Rf of +0.5 in 1:1 hexanes/ethyl acetate and no remaining startingindole. The reaction was poured into 500 mL of ethyl acetate and washedwith water (2×125 mL) and brine (2×125 mL). The organic layer was driedover magnesium sulfate and filtered. The filtrate was evaporated to ayellow oil which was dissolved in 50 ml 1:1 hexanes/ethyl acetate andfiltered through a plug of silica gel to remove baseline material. Thisleft 5.23 g of4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow oil (91% yield).

[0499] Step 2: 6.12 g of4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.098M, 1 eq.) and 1.12 g oftetrakis(triphenylphosphine) palladium (0) (0.001M, 0.1 eq.) were addedto 75 mL of THF. To the reaction 8.60 ml of morpholine (0.098M, 1 eq.)was added drop-wise over 20 min. After addition was complete thereaction was stirred at room temperature for 4 hours. The reaction waspoured into 250 mL of ethyl acetate and the organic solution wasextracted with 1N NaOH (2×75 mL). The aqueous layers were combined andacidified with 1N HCl, the acidic solution was extracted with ethylacetate (3×75 mL). The organic layers were combined and washed withbrine (1×50 mL), dried over magnesium sulfate, filtered and evaporatedto yield4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow oil (5.40 g, 97% yield).

[0500] Step 3: 400 mg of4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0007M, 1 eq.) was dissolved in 15 mL of methanol.To the solution, 80 mg of 5% platinum on activated carbon was added as aslurry in 5 mL of methanol. The black suspension was placed under ahydrogen atmosphere via a balloon and stirred for 24 hrs. at roomtemperature. The hydrogen was evacuated and another 80 mg of 5% platinumon activated carbon in 5 mL of methanol was added and the reaction wasagain placed under a hydrogen atmosphere via a balloon and stirred foranother 24 hrs. at room temperature. The reaction was monitored via NMRand at this point complete conversion was indicated. The reaction wasfiltered through Celite and the filtrate was evaporated to give4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow-green solid (320 mg, 79% yield).

[0501] Step 4: 100 mg of4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1 eq.) was dissolved in 1.0 ml of anhydrousmethylene chloride. To the solution 33.5 mg of oxalyl chloride (0.0003M,1.5 eq.) was added and the reaction stirred for one hour at roomtemperature. The reaction was then evaporated to dryness and the residuedissolved in 1.0 mL of anhydrous ethyl ether to which 0.027 mL of TMEDAwas added. To this solution 0.35 mL of zinc borohydride solution inether prepared by the literature method (Tet. Lett. Vol. 22, pg.4723,1981) was added. The reaction was stirred for 15 min. at roomtemperature and quenched with 1.0 mL of water. The reaction was dilutedwith 10 mL of ethyl ether and the water layer separated, the organiclayer was dried over magnesium sulfate, filtered and evaporated to aclear oil. The oil was chromatographed with ethyl acetate/hexanes (1:9)to result in isolation of4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a white foam (81 mg, 83% yield).

[0502] Step 5: 104.0 mg of4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1.0 eq.) was dissolved in 2.0 mL ofanhydrous methylene chloride. To the solution 116.0 mg of polystyrenebound triphenylphosphine was added (1.61 mmol/g, 0.0002M, 1.0 eq.)followed by 125.0 mg of carbon tetrabromide (0.0004M, 2 eq.). Thesuspension was stirred for 2 hrs at room temperature at which point thereaction was filtered and the filtrate evaporated to an orange oil. Theoil was purified via column chromatography with ethyl acetate/hexanes(2:98) to give 100 mg (86%) of4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester title as a yellow foam.

[0503] Step 6: 33.3 mg of □-toluene sulfonamide (0.0002M, 1.2 eq.) wasdissolved in 0.5 mL of DMF and added to a slurry of 8.0 mg of 60% sodiumhydride (0.0002M, 1.2 eq.) in 0.5 mL of DMF. The reaction was stirredfor 30 min. at which point 100 mg of4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1.0 eq.) in 0.5 mL of DMF was added and thesolution was stirred for an additional 1 hour. The reaction was quenchedwith water and diluted with 10 mL of ethyl acetate. The organic layerwas washed with water(2×5 mL) and brine (2×5 mL), dried over magnesiumsulfate and evaporated to a yellow oil. The residue was purified viacolumn chromatography (ethyl acetate/hexanes 5:95) to give 20 mg (17%)of4-{2-[1-Benzhydryl-5-chloro-2-(3-phenylmethanesulfonylamino-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacidmethyl ester as a clear oil.

[0504] Step 7: 20.0 mg of indole from Example 6 (0.00002M, 1 eq.) washydrolyzed as in Example 1 Step 8 to yield the title compound (13.0 mg,88% yield) m/z (M−1) 691.

[0505] The appropriately substituted halo amine is reacted with asuitable halide and a tertiary amine base to yield an N-alkylatedsubstrate for a Shonigishiru coupling (with an alkynol in the presenceof Pd^(ii) and a suitable base). This arylalkynol is cyclized to theindole under the action of a copper halide and heat. The free alcoholwas protected with a silyl protecting group by reaction with a silylchloride in the presence of a base such as imidazole. This indole wasnext C₃ acylated by reaction with a suitable acid chloride and theresulting compound reduced with most reducing agents but preferablyborane or a borane complex. The primary alcohol was then oxidized to analdehyde by any number of oxiidizing agents, including oxalylchloride/DMSO (swern conditions) or TPAP/NMO. This aldehyde wassubjected to reductive amination conditions, which include a borohydridereducing agent and in some cases a protice acid, and a primary orsecondary amine. The silyl ether was then deprotected with a flouridesource including CsF, TBAF, HF etc. This free alcohol was converted intoa leaving group, halide with CBr₄ and a phosphine, or a sulfonate esterwith methane sulfonyl chloride and a tertiary amine. The activatedalcohol is reacted with sodium azide in either DMF or DMSO to yield thedesired azide which in turn was reduced under Staudinger conditions,phosphine and THF/H₂O, or via hydrogenation using hydrogen and asuitable catalyst. The amine could be sulfonylated by the action of asulfonyl chloride under either biphasic Shcott and Baumman conditions,Aq. Bicarbonate and dichloromethane, or under anhydrous conditionsconsisting of dichloromethane and an organic base such as Hunigs base.The resulting intermediate was hydrolyzed using a base, NaOH, KOH, LiOHand a mixture of solvents including an alcoholic solvent, water andtetrahydrofuran.

[0506] The following Examples 143-151 were synthesized with Method N.

EXAMPLE 1434-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]amino}benzoicacid

[0507] Step 1: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1mmol) in DMF (250 mL) at rt were added □-bromodiphenylmethane (21.5 g,84.6 mmol) and ^(i)Pr₂NEt (23 mL, 130 mmol) and the reaction mixture washeated at 45° C. overnight. After the volatile was removed under reducedpressure, the residue was dissolved in EtOAc, washed with water (3×) andbrine and dried over MgSO₄. Purification on SiO₂ column chromoatography(hexanes to 5% EtOAc/hexanes) gave the desiredBenzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as ayellowish solid.

[0508] Step 2: A mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine(26.1 g, 62.2 mmol), PdCl₂(PPh₃)₂ (1.90 g, 2.67 mmol), Cul (1.2 g, 6.2mmol), 3-butyn-1-ol, and Et₃N (120 mL) was stirred at 45° C. for 20hours. The reaction mixture was filtered through celite and rinsed withEtOAc. The filtrate was concentrated, redissolved in EtOAc, washed withwater (3×) and brine, and dried over MgSO₄. The crude4-[2-(Benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) was usedin the next step directly without further purification.

[0509] Step 3: A solution of the crude4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and Cul(2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125° C. for 24 hours.The reaction mixture was filtered through celite and rinsed with EtOAc.The filtrate was concentrated, redissolved in EtOAc, washed with water(3×) and brine, and dried over MgSO₄. Silica gel column chromatography(30% EtOAc/hexanes) yielded the desired2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5g, 73% over 2 steps).

[0510] Step 4: To a solution of2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethanol (15.3 g, 42.3 mmol) inCH₂Cl₂ (190 mL) at 0° C. were added imidazole (3.72 g, 55.0 mmol) andTBDPSCl (13.2 mL, 50.8 mmol). After stirring at the same temperature for1.5 hours, the reaction mixture was washed with cold water (3×) andbrine, and dried over MgSO₄. The crude silyl ether was used in the nextstep directly without further purification.

[0511] Step 5: To a solution of the crude silyl ether in Et₂O (200 mL)at 0° C. was added oxalyl chloride (4.84 mL, 55.5 mmol) dropwise. Thereaction mixture was allowed to warm to rt and stirring continued for 4hours before Et₃N (35 mL) and MeOH (10 mL) were added. The mixture waswashed with water, brine, and dried over MgSO₄. The crude keto ester wasused directly in the next step.

[0512] Step 6: To the keto ester in THF (300 mL) was added BH₃.Me₂S (10M, 36 mL) dropwise at rt and the reaction mixture was refluxedovernight. The mixture was cooled at 0° C. before NaOH (30%, 150 mL) wasadded and stirring continued for 30 min. THF was removed under reducedpressure and the reaction mixture was extracted with EtOAc, washed withwater, brine, and dried over MgSO₄. Purification on columnchromatography (15 to 20% EtOAc/hexanes) yielded the desired product asa white solid (15.9 g, 24.7 mmol, 58% over 3 steps).

[0513] Step 7: To a solution of oxalyl chloride (0.372 mL, 4.27 mmol) inCH₂Cl₂ (10 mL) at −78° C. was added DMSO (0.661 mL, 9.31 mmol) dropwise.The reaction mixture was stirred at the same temperature for 5 minbefore a solution of2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(2.50 g, 3.88 mmol) in CH₂Cl₂ (8 mL) was introduced. After additional 40min stirring, ^(i)Pr₂NEt (3.38 mL, 19.4 mmol) was added and the reactionwas quenched with cold water (5 mL) and extracted with CH₂Cl₂. Theorganic layer was dried over MgSO₄ and evaporated. The crude{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehydewas used directly in the next step.

[0514] Step 8: To a solution of the crude aldehyde (3.88 mmol) in1,2-dichloroethane (39 mL) at 0° C. were added methyl 4-aminobenzoate(645 mg, 4.27 mmol), acetic acid (1.33 mL), and NaBH(OAc)₃. The reactionmixture was allowed to warm to rt overnight and quenched with coldNaHCO₃. An extractive workup furnished the desired4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoicacid methyl ester which was used directly in the next step withoutfurther purification.

[0515] Step 9: To4-(2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoicacid methyl ester (3.88 mmol) in THF (25 mL) at 0° C. was added amixture of HOAc:1M TBAF (in THF) (2.3 mL:5.8 mL) and the reactionmixture was allowed to stir at rt for 18 h. Extractive workup followedby trituration with 5% EtOAc/hex gave the desired4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester with slight impurity as an off-white solid (92%, over3 steps).

[0516] Step 10: To a solution of4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (1.64 g, 3.04 mmol) in CH₂Cl₂ at 0° C. were added Et₃N(0.636 mL, 4.56 mmol) and MsCl (0.282 mL, 3.64 mmol). After stirring atthe same temperature for 35 min, the reaction mixture was quenched withcold water. An extractive workup revealed the crude mesylate as anoff-white solid (1.70 g, 90%).

[0517] Step 11: A solution of the crude mesylate (1.70 g, 2.75 mmol) andNaN₃ (89 mg, 13.8 mmol) in DMF (14 mL) was stirred at 80° C. for 6 h.The reaction mixture was diluted with EtOAc and subjected to an aqueousworkup followed by flash column chromatography to yield the desired4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (813 mg, 52% yield).

[0518] Step 12: To4-{2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (400 mg, 0.709 mmol) in THF (4 mL) at 0 C. was addedPh₃P (223 mg, 0.851 mmol) in portions. The reaction mixture was stirredat rt for 11 h and 35° C. for 4 h before water (50 uL) was added andstirring continued overnight. The reaction mixture was diluted withEtOAc, dried with MgSO₄ and purified by flash column chromatography(EtOAc to 20%MeOH/EtOAc with 1% Et₃N) to give the desired4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (201 mg, 53%) as a solid.

[0519] Step 13: The intermediate from step 8 was treated with□-toluenesulfonyl chloride according to the procedure in Example 87 step2 to generate the desired product in 72% yield.

[0520] Step 14: The ester intermediate was hydrolyzed according to Step8 Example 1, to afford the title acid in 87% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S+H] 678.21879 found 678.2178.

EXAMPLE 1444-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

[0521] Step 1: The intermediate from example 142 step 12 was treatedwith 2-chloro-6-methyl-benzenesulfonyl chloride according to theprocedure in Example 87 step 2 to generate the desired product in 85%yield.

[0522] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₅Cl₂N₃O₄S+H] 712.17981 found 712.17895.

EXAMPLE 1454-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

[0523] Step 1: The intermediate from example 142 step 12 was treatedwith 2-methoxy-benzenesulfonyl chloride according to the procedure inExample 87 step 2 to generate the desired product in 85% yield.

[0524] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 92% yield. HRMS calc for[C₃₉H₃₆ClN₃O₅S+H] 694.2137 found 694.21311.

EXAMPLE 1464-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

[0525] Step 1: The intermediate from example 142 step 12 was treatedwith 2-chloro-benzenesulfonyl chloride according to the procedure inExample 87 step 2 to generate the desired product in 21% yield.

[0526] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₃Cl₂N₃O₄S+H] 698.16416 found 698.16365.

EXAMPLE 1474-[[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl](methyl)amino]benzoicacid

[0527] Step 1: Crude{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehydefrom step 7, example 142 was treated with 4-Methylamino-benzoic acidmethyl ester according to the procedure in Example 142 step 8 to yieldthe desired4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoicacid methyl ester in 73% yield.

[0528] Step 2: The title compound was prepared according to theprocedure described for Example 142 step 9. The crude4-({2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester was used in the next step directly without furtherpurification.

[0529] Step 3-6:4-({2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester was prepared according to the procedure described forexample 142 steps 10-12 in 61% (3 steps).

[0530] Step 7: A solution of4-({2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester (410 mg, 0.709 mmol) and 10% Pd/C (155 mg) inMeOH:CH₂Cl₂ (=7 mL:1 mL) was stirred under H₂ atmosphere (1 atm) for 2 h15 min. The reaction mixture was filtered through celite and rinsed withMeOH and CH₂Cl₂. Flash column chromatography (CH₂Cl₂ to 8% MeOH/CH₂Cl₂)of the residue gave the desired4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester in 78% yield (305 mg).

[0531] Step 8: The intermediate from step 7 was treated with□-toluenesulfonyl chloride according to the procedure in Example 87 step2 to generate the desired product in 83% yield.

[0532] Step 9: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 91% yield. HRMS calc for[C₃₉H₃₈ClN₃O₄S+H] 692.23444 found 692.23374.

EXAMPLE 1484-[{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

[0533] Step 1: The intermediate from example 146 step 7 was treated with3,4-dichlorophenylmethanesulfonylchloride according to the procedure inExample 87 step 2 to generate the desired product in 87% yield.

[0534] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 68% yield. HRMS calc for[C₄₀H₃₆Cl₃N₃O₄S+H] 760.15649 found 760.1573.

EXAMPLE 1494-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

[0535] Step 1: The intermediate from example 146 step 7 was treated with2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure inExample 87 step 2 to generate the desired product in 96% yield.

[0536] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 88% yield. HRMS calc for[C₄₀H₃₇Cl₂N₃O₄S+H] 726.19546 found 726.19461.

EXAMPLE 1504-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

[0537] Step 1: The intermediate from example 146 step 7 was treated with2-chlorobenzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 96% yield.

[0538] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 84% yield. HRMS calc for[C₃₉H₃₅Cl₂N₃O₄S+H] 712.17981 found 712.17966.

EXAMPLE 1514-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

[0539] Step 1: The intermediate from example 146 step 7 was treated with2-methoxy-benzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 95% yield.

[0540] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 73% yield. HRMS calc for[C₄₀H₃₈ClN₃O₅S+H] 708.22935 found 708.2286.

EXAMPLE 1524-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0541] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 95% yield.

[0542] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 77% yield. HRMS calc forC₃₉H₃₃Cl₃N₂O₄S, 730.1227; found (ESI+), 731.1299.

EXAMPLE 1534-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0543] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,6-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 93% yield.

[0544] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 71% yield. HRMS calc forC₃₉H₃₃Cl₃N₂O₄S, 730.1227; found (ESI+), 731.13005.

EXAMPLE 1544-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0545] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4,6-trichlorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 76% yield.

[0546] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 84% yield. HRMS calc forC₃₉H₃₂Cl₄N₂O₄S, 764.0837; found (ESI+), 765.08981.

EXAMPLE 1554-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0547] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-cyanobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 87%yield.

[0548] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 and purified by prep HPLC to afford the title acid in 8%yield. HRMS calcd for C₄₀H₃₄ClN₃O₄S, 687.1959; found (ESI+), 688.2019.

EXAMPLE 1564-(3-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}propyl)benzoicacid

[0549] Step 1: Methyl4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate(Example 154, Step 1, 0.43 g, 0.61 mmol) was dissolved in THF (4 mL) andMeOH (12 mL). Cobalt (II) chloride (0.16 g, 1.2 mmol) and NaBH₄ (0.23 g,6.1 mmol) were added. After 2 h the mixture was filtered, concentrated,and chromatographed on silica gel (MeOH—CH₂Cl₂) to afford the aminoester in 13% yield.

[0550] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 59% yield. HRMS calcd forC₃₉H₃₆ClN₃O₅S, 693.2064; found (ESI+), 694.21261

EXAMPLE 1574-[3-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoicacid

[0551] Step 1: 2-Bromobiphenyl (0.55 mL, 3.2 mmol) was dissolved in THF(10 mL) and Et₂O (10 mL) and cooled at −78° .C while n-BuLi (1.3 mL of2.5 M solution in hexanes, 3.2 mmol) was added rapidly dropwise. After40 min, the mixture was added via cannula to a −78° C. solution of SO₂(10 mL) in Et₂O (20 mL). The mixture was warmed to room temperatureovernight, concentrated, and triturated with Et₂O. The resulting whitesolid was suspended in hexane (40 mL) and cooled at 0° C. Sulfurylchloride (3.4 mL of 1.0 M soln. in CH₂Cl₂, 3.4 mmol) was added and themixture was stirred at room temperature for 5 h. It was thenconcentrated to afford 2-biphenylsulfonyl chloride in 67% yield.

[0552] Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-biphenylsulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 83% yield.

[0553] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calcd forC₄₅H₃₉ClN₂O₄S, 738.2319; found (ESI+), 739.23825.

EXAMPLE 1584-{3-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoicacid

[0554] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-bromobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 76%yield.

[0555] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calcd forC₃₉H₃₄BrClN₂O₄S, 740.1111; found (ESI+), 741.11696.

EXAMPLE 1594-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0556] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4-dichlorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 83% yield.

[0557] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 80% yield. HRMS calc forC₃₈H₃₁Cl₃N₂O₅S, 732.1019; found (ESI+), 733.10824.

EXAMPLE 1604-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0558] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-dichlorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 77% yield.

[0559] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc forC₃₈H₃₁Cl₃N₂O₅S, 732.1019; found (ESI+), 733.10836.

EXAMPLE 1614-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0560] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4,6-trichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 90% yield.

[0561] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 87% yield. HRMS calcd forC₃₈H₃₀Cl₄N₂O₅S, 766.0630; found (ESI+), 767.07063.

EXAMPLE 1624-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0562] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-cyanobenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 82% yield.

[0563] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 and purified by prep HPLC to afford the title acid in 17%yield. HRMS calcd for C₃₉H₃₂ClN₃O₅S, 689.1751; found (ESI+), 690.18082.

EXAMPLE 1634-(2-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

[0564] Step 1: Methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate(Example 161, Step 1, 0.31 g, 0.44 mmol) was dissolved in THF (4 mL) andMeOH (12 mL). Cobalt (II) chloride (0.11 g, 0.88 mmol) and NaBH₄ (0.17g, 4.4 mmol) were added. After 2 h the mixture was filtered,concentrated, and chromatographed on silica gel (MeOH—CH₂Cl₂) to affordthe amino ester in 17% yield.

[0565] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 39% yield. HRMS calcd forC₃₉H₃₆ClN₃O₅S, 693.2064; found (ESI+), 694.21261.

EXAMPLE 1644-[2-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0566] Step 1: The sulfonamide was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-biphenylsulfonyl chloride (Step 1, Example156) according to the procedure in Example 1 Step 7 in 93% yield.

[0567] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calcd forC₄₄H₃₇ClN₂O₅S, 740.2112; found (ESI+), 741.21709.

EXAMPLE 1654-{2-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

[0568] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-bromobenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 90% yield.

[0569] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calcd forC₃₈H₃₂BrClN₂O₅S, 742.0904; found (ESI+), 743.09697.

EXAMPLE 1664-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0570] Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 5-chloro-2,4-difluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 68% yield.

[0571] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 44% yield. HRMS calc for[C₃₉H₃₂Cl₂F₂N₂O₄S+H] 733.15007 found 733.14978.

EXAMPLE 1674-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0572] Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methoxy-4-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 86% yield.

[0573] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 39% yield. HRMS calc for[C₄₁H₃₉ClN₂O₅S+H] 707.2341 found 707.23407.

EXAMPLE 1684-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0574] Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4-chloro-2,5-difluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 79% yield.

[0575] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 63% yield. HRMS calc for[C₃₉H₃₂Cl₂F₂N₂O₄S+H] 733.15007 found 733.14882.

EXAMPLE 1694-{2-[1-Benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0576] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 5-chloro-2,4-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 38% yield.

[0577] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 31% yield. HRMS calc for[C₃₈H.₃₀Cl₂F₂N₂O₅.S+H] 735.12933 found 735.12824.

EXAMPLE 1704-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0578] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-2,5-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 79% yield.

[0579] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 63% yield. HRMS calc for[C₃₈H.₃₀Cl₂F₂N₂O₅.S+H] 735.12933 found 735.12913.

EXAMPLE 1714-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0580] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methoxy-2-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7.

[0581] Step 2: The crude ester intermediate was hydrolyzed according toStep 8 Example 1 to afford 407 mg of the title acid in quantitativeyield. HRMS calc for [C₄₀H.₃₇ClN₂O₆.S+H] 709.21337 found 709.21194.

EXAMPLE 1724-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0582] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole according to theprocedure in Example 1 Step 7 to generate the product in 43% yield.

[0583] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 26% yield after HPLC separation.HRMS calc for [C₃₉H₃₂Cl₂N₄O₅S+H] 739.15433 found 739.1537.

EXAMPLE 1734-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0584] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole according to theprocedure in Example 1 Step 7 to generate the product in 43% yield.

[0585] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 36% yield after HPLC separation.HRMS calc for [C₄₀H₃₅ClN₄O₆S+H] 735.2046 found 735.2029.

EXAMPLE 1744-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0586] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazoleaccording to the procedure in Example 1 Step 7 in 56% yield.

[0587] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 30% yield after HPLC separation.HRMS calc for [C₃₆H.₃₀Cl₂N₄O₆.S+H] 741.1343 found 741.1328.

EXAMPLE 1754-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0588] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazoleaccording to the procedure in Example 1 Step 7 in 56% yield.

[0589] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 36% yield after HPLC separation.HRMS calc for [C₃₉H.₃₃ClN₄O₇.S+H] 737.1838 found 737.1819.

EXAMPLE 1764-(3-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

[0590] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added5-(2-methyl-1,3-thiazol-4-yl)-thiophene-2-sulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 90% yield.

[0591] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₁H₃₆ClN₃O₄S₃+H] 766.1636 found 766.1629.

EXAMPLE 1774-(2-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0592] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and5-(2-methyl-1,3-thiazol-4-yl)-thiophene-2-sulfonyl chloride according tothe procedure in Example 1 Step 7 in 100% yield.

[0593] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₄₀H₃₄ClN₃O₅.S₃-H] 767.1269 found 766.1259.

EXAMPLE 1784-[2-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0594] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-thiophenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 91% yield.

[0595] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₆H₃₁ClN₂O₅.S₂+H] 671.14357 found 671.1428.

EXAMPLE 1794-{2-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0596] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 6-morpholino-3-pyridinesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 91% yield.

[0597] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₄₁H₃₉ClN₄O₆.S+H] 751.23516 found 751.2345.

EXAMPLE 1804-[3-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0598] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 3-thiophenesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 87% yield.

[0599] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₃₇H₃₃ClN₂O₄S₂+H] 669.16431 found 669.1629:

EXAMPLE 1814-{3-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0600] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 6-morpholino-3-pyridinesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 79% yield.

[0601] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₄₂H₄₁ClN₄O₅S+H] 749.2559 found 749.255.

EXAMPLE 1824-(2-{1-Benzhydryl-2-[2-(benzo[1,2,5]oxadiazole-4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoicacid

[0602] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and benzofuran-4-sulfonyl chloride according to theprocedure in Example 1 Step 7 in 88% yield.

[0603] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₁ClN₄O₆S+H] 707.17256 found 707.1719.

EXAMPLE 1834-(3-{1-Benzhydryl-2-[2-(benzo[1,2,5]oxadiazole4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoicacid

[0604] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added benzofuran-4-sulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 69%yield.

[0605] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. HRMS calc for[C₃₉H₃₃ClN₄O₅S+H] 705.1933 found 705.1931.

EXAMPLE 1844-(2-{1-Benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoicacid

[0606] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-benzyloxy-benzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 87% yield.

[0607] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₄₅H₃₉ClN₂O₆S−H] 769.21446 found 769.2129.

EXAMPLE 1854-(2-{1-Benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)benzoicacid

[0608] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-isopropoxybenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 88% yield.

[0609] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield after trturation withethylether. HRMS calc for [C₄₁H₃₉ClN₂O₆S+H] 723.22902 found 723.2284.

EXAMPLE 1864-(3-{1-Benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

[0610] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-isopropoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 71% yield.

[0611] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield after HPLC purification.HRMS calc for [C₄₂H₄₁ClN₂O₅S+H] 721.24975 found 721.2490.

EXAMPLE 1874-(3-{1-Benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoicacid

[0612] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-benzyloxy-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 57% yield.

[0613] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield after HPLC purification.HRMS calc for [C₄₆H₄₁ClN₂O₅S+H] 769.2505 found 769.2494.

EXAMPLE 1884-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

[0614] Step 1: The benzyl group from step 1 Example 186 was removed byhydrogenolysis. The crude was purified on silica gel column withCH₂Cl₂-5% EtOAc/CH₂Cl₂, to get a mixture which was further purified byHPLC to obtain4-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester (7%) and4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester (18%) Step 2: The4-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. HRMS calc for[C₃₉H₃₆N₂O₅S+H] 645.2418 found 645.2423.

EXAMPLE 1894-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

[0615] Step 1:4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester intermediate from step 1 of Example 187 was hydrolyzedaccording to Step 8 Example 1 to afford the title acid in 86% yield.HRMS calc for [C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.2038.

EXAMPLE 1904-(2-{1-Benzhydryl-5-chloro-2-[2-(2-chloro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid

[0616] Step 1: To a solution of Ph3P (698 mg, 2.7 mmole, 2.0 equiv.) inTHF (10 ml) was slowly introduced diisopropylazodicarboxylate (0.55 ml,2.7 mmole, 2.0 equiv.) at 0° C. under N₂. It was allowed to stir for 15min. A solution of2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(859 mg, 1.3 mmole, 1.0 equiv. Step 6, Example 142) in THF (5 ml) wastransferred to Mitsunobu reagents, followed by2-fluoro-4-hydroxy-benzoic acid methyl ester (340 mg, 2.0 mmole, 1.5equiv.). The resulted solution was stirred overnight. THF was removed.The residues were partitioned between EtOAc and water. The organic phasewas washed with water and brine, dried over MgSO₄. The product waspurified on silica gel column with 8% EtOAc/hexane. 0.95 g (90%) ofproduct was obtained as a white solid.

[0617] Step 2: The4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid methyl ester was deprotected according to the procedure in Example142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester in 89% yield.

[0618] Step 3:4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester was activated by conversion to the mesylate followingthe procedure in Step 10 Example 142 and the resulting product was usedcrude in the next step.

[0619] Step 4: The mesylate from above was displaced with azide asdescribed in Step 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester in 97% yield (over two steps).

[0620] Step 5: The4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester was reduced under Staudinger conditions to yieldmethyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoatein 93% yield.

[0621] Step 6: The methyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoatefrom above and 2-chloro-benzenesulfonyl chloride were reacted accordingto the procedure in Example 1 Step 7 to generate the desired product in73% yield.

[0622] Step 7: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₈H₃₁Cl₂FN₂O₅S+H] 717.13876 found 717.1365.

EXAMPLE 1914-(2-{1-Benzhydryl-5-chloro-2-[2-(2-chloro-6-methyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid

[0623] Step 2: This compound was prepared from methyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate(Step 5, Example 189) and 2-chloro-6-methyl-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 66% yield.

[0624] Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield HRMS calc for[C₃₉H₃₃Cl₂FN₂O₅S+H] 731.15441 found 731.1532.

EXAMPLE 192N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methanesulfonamide

[0625] Step 1: The2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142) was coupled with 4-Hydroxy-benzonitrile accordingto the conditions described in Example 189, Step 1 to yield4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzonitrilein 85% yield.

[0626] Step 2: The silyl ether from above was deprotected following theExample 142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzonitrilein 93% yield.

[0627] Step 3: The alcohol from above was activated by conversion to themesylate as described in Step 10 Example 142 to yield the desiredmesylate which was used without purification in the next step.

[0628] Step 4: The mesylate from above was treated under the conditionsdescribed in Step 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzonitrilein 91% yield (2 steps).

[0629] Step 5:4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzonitrilewas reduced under Staudinger conditions as detailed in Step 12, example142 to yield4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrilein 92% yeild.

[0630] Step 6: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrilefrom above and (3,4-dichloro-phenyl)-methanesulfonyl chloride werereacted according to the procedure in Example 1 Step 7 to yield thedesired product in 92% yield.

[0631] Step 7: The mixture of nitrile (1.0 equiv.), azidotrimethylsilane(2.0 equiv.), dibutyltin oxide (0.1 equiv.) and toluene (3.3 ml/mmole)in a sealed tube was heated at 120° C. for 20 hours. It was acidifiedwith 1 N HCl at room temperature, then diluted with EtOAc. The organicphase was washed with water and brine, dried over MgSO₄. The crudetetrazole was chromatographed with 50% EtOAc/hexanes−80% EtOAc/hexanesplus 0.5% of acetic acid to afford the title product in 58% yield HRMScalc for [C₃₉H₃₃Cl₃N₆O₃S+H] 771.14732 found 771.1475.

EXAMPLE 193N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]-ethyl}-1H-indol-2-yl)-ethyl]-2-chlorobenzenesulfonamide

[0632] Step 1:4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 2-chloro-benzenesulfonyl chloride were reactedaccording to the procedure in Example 1 Step 7 to yield the desiredproduct in 77% yield.

[0633] Step 2: The nitrile from above was converted to tetrazoleaccording to Step 7 of Example 191 to afford the title product in 45%yield. HRMS calc for [C₃₈H₃₂Cl₂N₆O₃S+H] 723.17065 found 723.1711.

EXAMPLE 194N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]butane-1-sulfonamide

[0634] Step 1: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 1-butanesulfonyl chloride where reactedaccording to the procedure in Example 1 Step 7 to yield the product in79% yield.

[0635] Step 2: The nitrile was converted to tetrazole according to Step7 of Example 191 to afford the title product in 91% yield HRMS calc for[C₃₆H₃₇ClN₆O₃S+H] 669.24092 found 669.2409.

EXAMPLE 195N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2,2,2-trifluoroethanesulfonamide

[0636] Step 1: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 2,2,2-trifluoro-ethanesulfonyl chloride wherereacted according to the procedure in Example 1 Step 7 to yield thedesired product in 64% yield.

[0637] Step 2: The nitrile was converted to tetrazole according to Step7 of Example 191 to afford the title product in 77% yield HRMS calc for[C₃₄H₃₀ClF₃N₆O₃S+H] 695.18135 found 695.1807.

EXAMPLE 1964-(2-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0638] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4,6-trifluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 92% yield.

[0639] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₈H₃₀ClFN₂O₃S+H] 719.15889 found 719.15843.

EXAMPLE 1974-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0640] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-methoxy-2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 74% yield.

[0641] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₉H₃₄ClN₃O₈S+H] 740.1828 found 740.1834.

EXAMPLE 1984-(2-{1-Benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0642] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-(trifluoromethoxy)benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0643] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₃₉H₃₂ClF₃N₂O₆S+H] 771.1514 found 771.1512.

EXAMPLE 1994-(3-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl)-propyl)-benzoicacid

[0644] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4,6-trifluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 61% yield.

[0645] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. HRMS calc for[C₃₉H₃₂ClF₃N₂O₄S+H] 717.17962 found 717.17913.

EXAMPLE 2004-(3-{1-Benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

[0646] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 4-methoxy-2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 81% yield.

[0647] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₄₀H₃₆ClN₃O₇S+H] 738.2035 found 738.2028.

EXAMPLE 2014-(3-{1-Benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

[0648] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 4-methoxy-2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 83% yield.

[0649] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.19019 found 747.18996.

EXAMPLE 2024-{2-[1-Benzhydryl-5-chloro-2-{2-[({4-methysulfonylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0650] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 4-methysulfonybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0651] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₆S₂ +H] 741.18544 found 741.18421.

EXAMPLE 2034-[2-(1-Benzhydryl-2-{2-[(4-methylsulfonylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0652] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-methylsulfonylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0653] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H.₃₅ClN₂O₇S₂−H] 741.15014 found 741.14842.

EXAMPLE 2044-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-methylsulfonylbenzene}-sulfonyl)aminolethyl}-1H-indol-3-yl)propylibenzoicacid

[0654] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methylsulfonybenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0655] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₆S₂+H] 741.18544 found 741.18425.

EXAMPLE 2054-[2-(1-Benzhydryl-2-{2-[(2-methylsulfonylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0656] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

[0657] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H.₃₅ClN₂O₇S₂+H] 743.16470 found 743.16431.

EXAMPLE 2064-{2-[1-Benzhydryl-5-chloro-2-{2-[({3-phenylsulfonylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0658] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-phenylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0659] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₅H₃₉ClN₂O₄S+H] 739.23919 found 739.23896.

EXAMPLE 2074-[2-(1-Benzhydryl-2-{2-[(3-phenylsulfonylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0660] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-phenylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

[0661] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₄H.₃₇ClN₂O₅S+H] 741.21845 found 741.21879.

EXAMPLE 2084-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-trifluoromethylsulfonylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0662] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and2-trifluoromethylsulfonybenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 65% yield.

[0663] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₄F₃ClN₂O₅S+H] 731.19527 found 731.19591.

EXAMPLE 2094-[2-(1-Benzhydryl-2-{2-[(2-trifluoromethylsulfonylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0664] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0665] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₀H₃₄F₃ClN₂O₄S₂+H] 733.17454 found 733.17439.

EXAMPLE 2104-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0666] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 5-Methyl-1-phenyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 93% yield.

[0667] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₄₃H₃₉ClN₄O₄S+H] 743.24533 found 743.24506.

EXAMPLE 2114-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0668] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 5-Methyl-1-phenyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 88% yield.

[0669] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₃₇ClN₄O₅S+H] 745.2246 found 745.22362.

EXAMPLE 2124-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0670] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 1 ,5-Dimethyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 92% yield.

[0671] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₉H₃₉ClN₄O₄S+H] 695.24533 found 695.24453.

EXAMPLE 2134-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0672] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was 1,5-Dimethyl-1H-pyrazole-4-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 100% yield.

[0673] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield. HRMS calc for[C₃₈H₃₇ClN₄O₅S+H] 697.2246 found 697.2241.

EXAMPLE 2144-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0674] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2,3-Dichloro-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 85% yield.

[0675] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₄S −H] 729.1154 found 729.1135.

EXAMPLE 2154-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0676] Step 1: To the4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 2,3-Dichloro-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 79% yield.

[0677] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. HRMS cale for[C₃₈H₃₁Cl₃N₂O₅S −H] 731.0947 found 731.0930.

EXAMPLE 2164-{3-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0678] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4′-fluorophenyl-4-benzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0679] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₅H₃₈ClFN₂O₄S+H] 757.22976 found 757.22874.

EXAMPLE 2174-{2-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0680] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4′-fluorophenyl-4-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0681] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₄H₃₆ClFN₂O₅S+H] 759.20903 found 759.20745.

EXAMPLE 2184-{2-[1-Benzhydryl-5-chloro-2-{2-[({3-trifluoromethylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0682] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-trifluoromethylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0683] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₄S+H] 731.19527 found 731.19582.

EXAMPLE 2194-[2-(1-Benzhydryl-2-{2-[(3-trifluoromethylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0684] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0685] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF3N₂O₅S+H] 733.17454 found 733.17431.

EXAMPLE 2204-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0686] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step1, was added 3,4-dichlorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 24% yield of ester and 14% of acid.

[0687] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. m/z (M−1)779.01.

EXAMPLE 2214-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-fluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0688] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step1, was added 3-chloro-4-flurothiophenol according to theprocedure in Example 81 step 2. The product was purified by flash columnwith 30% EtOAc/hexanes in 70% yield.

[0689] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. m/z (M−1)760.94.

EXAMPLE 2224-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-fluorobenzene}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0690] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-fluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0691] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₉H₃₄ClFN₂O₄S+H] 681.19846 found 681.19854.

EXAMPLE 2234-[2-(1-Benzhydryl-2-{2-[(2-fluorobenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0692] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-fluorobenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

[0693] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₃ClFN₂O₅S+H] 683.17773 found 683.17694.

EXAMPLE 2244-{2-[1-Benzhydryl-5-chloro-2-{2-[({2,6-difluorobenzene}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0694] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,6-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0695] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂O₄S+H] 699.18904 found 699.18850.

EXAMPLE 2254-[2-(1-Benzhydryl-2-{2-[(2,6-difluorobenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0696] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-difluorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

[0697] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₂ClF₂N₂O₅S+H] 701.16831 found 701.16849.

EXAMPLE 2264-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-chloro-6-methylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0698] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-chloro-6-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0699] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.18456 found 711.18404.

EXAMPLE 2274-[2-(1-Benzhydryl-2-{2-[(2-chloro-6-methylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0700] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-chloro-6-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0701] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂O₅S+H] 713.16383 found 713.16269.

EXAMPLE 2284-{2-[1-Benzhydryl-5-chloro-2-{2-[({4-trifluoromethylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0702] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4-trifluoromethylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0703] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₄S+H] 731.19527 found 731.19580.

EXAMPLE 2294-[2-(1-Benzhydryl-2-{2-[(4-trifluoromethylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0704] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0705] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF₃N₂O₅S+H] 733.17454 found 733.17432.

EXAMPLE 2304-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-trifluoromethoxybenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0706] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-trifluoromethoxybenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0707] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₅S+H] 747.19019 found 747.18848.

EXAMPLE 2314-[2-(1-Benzhydryl-2-{2-[(2-trifluoromethoxybenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0708] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-trifluoromethoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0709] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF₃N₂O₆S+H] 749.16945 found 749.16813.

EXAMPLE 2324-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-methylbenzene}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0710] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0711] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₄S+H] 677.22354 found 677.22244.

EXAMPLE 2334-[2-(1-Benzhydryl-2-{2-[(2-methylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0712] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

[0713] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.20280 found 679.20197.

EXAMPLE 2344-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-methoxybenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0714] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0715] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₅S+H] 693.2185 found 693.21852.

EXAMPLE 2354-[2-(1-Benzhydryl-2-{2-[(2-methoxybenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0716] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methoxybenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

[0717] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₆S+H] 695.19722 found 695.19701.

EXAMPLE 2364-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-tert-butylbenzene}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0718] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-tert-butylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

[0719] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₃H₄₃ClN₂O₄S+H] 719.27049 found 719.27057.

EXAMPLE 2374-[2-(1-Benzhydryl-2-{2-[(2-tert-butylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0720] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-tert-butylbenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

[0721] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₂H₄₁ClN₂O₅S+H] 721.24975 found 721.24907.

EXAMPLE 2384-{2-[1-Benzhydryl-5-chloro-2-{2-[((2-methylthiobenzene}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0722] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-20yl]propyl}benzoate (Step 6, Example 42) was added and2-methylthiobenzenesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 65% yield.

[0723] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₄S₂+H] 25 709.19561 found 709.19504.

EXAMPLE 2394-[2-(1-Benzhydryl-2-{2-[(2-methylthiobenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0724] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylthiobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

[0725] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S₂+H] 711.17487 found 711.17518.

EXAMPLE 2404-{2-[1-Benzhydryl-5-chloro-2-(2-[({3-chloro-2-methylbenzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid

[0726] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-chloro-2-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

[0727] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.18456 found 711.18465.

EXAMPLE 2414-[2-(1-Benzhydryl-2-{2-[(3-chloro-2-methylbenzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0728] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-chloro-2-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

[0729] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂O₅S+H] 713.16383 found 713.16296.

EXAMPLE 2424-[2-(2-{2-[2-(4-Acetyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

[0730] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 1-acetylpiperazine according to the procedure inExample 100 step 2 except that it was heated at 60° C. for 19 h in 91%yield.

[0731] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 19% yield. m/z (M−1) 741.2

EXAMPLE 2434-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

[0732] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and cis-2,6-dimethylpiperazine according to theprocedure in Example 100 step 2 except that it was heated at 60° C. for19 h in 97% yield.

[0733] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 39% yield. m/z (M−1) 727.2

EXAMPLE 2444-[2-(2-{2-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

[0734] Step 1: To a solution of4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid methyl ester (Step 1, Example above) (31 mg, 0.042 mmol) in CH₂Cl₂(1 mL) at 0° C. were added Et₃N (0.10 mL) and Ac₂O (60 uL) and thereaction mixture was stirred at rt for 4 h. Aqueous workup followed bysilica gel chromatography (3.5% MeOH/MeOH) gave the desired esterintermediate (17 mg, 52% yield).

[0735] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 96% yield. m/z (M−1) 771.2.

EXAMPLE 2454-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0736] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 1-acetylpiperazine 4-methylpiperidine accordingto the procedure in Example 100 step 2. The product was purified by theflash column with 50-60% EtOAc/hexane in 87% yield.

[0737] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 91% yield. m/z (M−1)712.3.

EXAMPLE 2464-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0738] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 3-methylpiperidine according to the procedure inExample 100 step 2. The product was purified by the flash column with50-60% EtOAc/hexane in 94% yield.

[0739] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 87% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S+H] 714.2763 found714.2765.

EXAMPLE 2474-[2-(1-Benzhydryl-2-{2-[2-(2-carbamoyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

[0740] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and L-prolinamide according to the procedure inExample 100 step 2. The product was purified by the flash column withEtOAc in 86% yield.

[0741] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 43% yield after preparative HPLC purification. HRMS calc for[C₃₉H₄₁ClN₄O₆S+H] 729.2508 found 729.251.

EXAMPLE 2484-[2-(1-benzhydryl-5-chloro-2-(2-[({2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0742] Step 1: The compound was prepared from the intermediate Example100 step 1 and (S)-(+)-2-(methoxymethyl)pyrrolidine according to theprocedure Example 100 step 2. The product was purified by the flashcolumn with 80% EtOAc/hexane in 87 % yield.

[0743] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 87% yield. HRMS calc for [C₄₀H₄₄ClN₃O₆S+H] 730.2712 found730.2709.

EXAMPLE 2494-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-ethylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl)ethoxy)benzoicacid

[0744] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 2-ethylpiperidine according to the procedure inExample 100 step 2. The product was purified by the flash column with50-60% EtOAc/hexane in 73% yield.

[0745] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 38% yield after preparative HPLC purification. HRMS calc for[C₄₁H₄₆ClN₃O₅S+H] 728.292 found 728.2925.

EXAMPLE 2504-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(3R,5S)-3,5-dimethylmorpholin4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0746] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and cis-2,6-dimethylmorpholine according to theprocedure Example 100 step 2. The product was purified by the flashcolumn with 50% EtOAc/hexane in 79% yield.

[0747] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 94% yield. m/z (M−1) 729.4

EXAMPLE 2514-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0748] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and (1S, 4S)-(+)-2-aza-5-oxabicyclo-[2.2.1]-heptanehydrochloride according to the procedure in Example 100 step 2. Theproduct was purified on the CombiFlash with 1-7% MeOH/CH₂Cl₂ in 85%yield.

[0749] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 100% yield. HRMS calc for [C₃₉H₄₀ClN₃O₆S+H] 714.2399 found714.2397.

EXAMPLE 2524-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-isopropylpyrrolidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0750] Step 1: The compound was prepared from the intermediate fromExample 100 step 1 and 2-(methylethyl)-pyrrolidine hydrochlorideaccording to the procedure Example 100 step 2. The product was purifiedon the CombiFlash with 1-5% MeOH/CH₂Cl₂ in 61% yield.

[0751] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 97% yield. HRMS calc for [C₄₁H₄₆ClN₃O₅S+H] 728.292 found728.293.

EXAMPLE 2534-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperazin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0752] Step 1: The compound was prepared from the intermediate from fromExample 100 step 1 and 3-methyl-2-piperazinone according to theprocedure in Example 100 step 2. The product was purified by the flashcolumn with 5% MeOH/CH₂Cl₂ in 80% yield.

[0753] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 29% yield after preparative HPLC purification. HRMS calc for[C₃₉H₄₁ClN₄O₆S+H] 729.2508 found 729.2501.

EXAMPLE 2544-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0754] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 1) was added 2-chlorobenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to generate the product in 66%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.94 (m, 2 H), 2.74 (m, 6 H), 2.97(m, 2 H), 3.91 (s, 3 H), 4.94 (t, J=6.32 Hz, 1 H), 6.48 (d, J=9.09 Hz, 1H), 6.79 (dd, J=8.84, 2.02 Hz, 1 H), 6.83 (s, 1 H), 7.03 (m, 4 H), 7.26(m, 9 H), 7.39 (d, J=2.02 Hz, 1 H), 7.44 (d, J=3.54 Hz, 2 H), 7.90 (d,J=7.58 Hz, 1 H), 7.96 (d, J=8.34 Hz, 2 H)

[0755] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford, after flash chromatography, the title acid in84% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.96 (m, 2 H), 2.76 (m, 6 H),2.98 (m, 2 H), 5.00 (t, J=6.32 Hz, 1 H), 6.79 (dd, J=8.84, 2.02 Hz, 1H), 6.84 (s, 1 H), 7.04 (m, 4 H), 7.28 (m, 10 H), 7.40 (d, J=1.77 Hz, 1H), 7.45 (d, J=3.79 Hz, 2 H), 7.90 (d, J=7.58 Hz, 1 H), 8.02 (d, J=8.34Hz, 2 H). HRMS calc for C₃₉H₃₄Cl₂N₂O₄S Na, 719.1514; found (ESI−),695.15363

EXAMPLE 2554-{2-[1-benzhydryl-5-chloro-2-(2-{([(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0756] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-chlorobenzenesulfonyl chloride according to the procedure inExample 1, Step 7 in 86% yield. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.93 (m,2 H), 3.02 (m, 2 H), 3.11 (t, J=6.57 Hz, 2 H), 3.81 (s, 3 H), 4.19 (t,J=6.57 Hz, 2 H), 6.49 (d, J=8.84 Hz, 1 H), 6.80 (dd, J=8.84, 2.02 Hz, 1H), 6.96 (d, J=8.84 Hz, 2 H), 7.01 (s, 1 H), 7.04 (dd, J=6.95, 2.40 Hz,4 H), 7.34 (m, 5 H), 7.40 (m, 1 H), 7.60 (m, 3 H), 7.80 (dd, J=7.83,1.52 Hz, 1 H), 7.86 (d, J=8.84 Hz, 2 H), 8.11 (t, J=5.81 Hz, 1 H).

[0757] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1. The crude material was purified via flash chromatographyto afford the title acid in 74% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm2.89 (m, 2 H), 3.18 (t, J=6.57 Hz, 2 H), 4.20 (t, J=6.57 Hz, 2 H), 5.09(t, J=6.32 Hz, 1 H), 6.53 (d, J=8.84 Hz, 1 H), 6.82 (m, 3 H), 6.90 (s,1H), 7.05 (m, 4 H), 7.26 (m, 7 H), 7.45 (m, 2 H), 7.52 (d, J=2.02 H),7.90 (m, 1 H), 8.00 (d, J=8.84 Hz, 2 H). HRMS calc for C₃₈H₃₂Cl₂N₂O₅S,698.1409; found (ESI+), 699.14786. Anal. Calcd for C₃₈H₃₂Cl₂N₂05S: C,65.23; H, 4.61; N, 4.00. Found: C, 65.02; H, 4.44; N, 3.94.

EXAMPLE 2564-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

[0758] Step 1: This compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-benzoicacid methyl ester and 2-chlorosulfonyl chloride according to theprocedure in Example 1, Step 7 in 48% yield. ¹H NMR (400 MHz, CDCl₃) δppm 2.88 (q, J=7.07 Hz, 2 H), 3.03 (t, J=7.33 Hz, 2 H), 3.20 (m, 2 H),3.43 (m, 2 H), 3.97 (s, 3 H), 5.18 (t, J=6.44 Hz, 1 H), 6.46 (d, J=8.84Hz, 1 H), 6.78 (dd, J=8.97, 2.15 Hz, 1 H), 6.84 (s, 1 H), 7.04 (dd,J=6.69, 2.40 Hz, 4 H), 7.21 (d, J=2.02 Hz, 1 H), 7.31 (m, 7 H), 7.48 (d,J=3.79 Hz, 2 H), 7.91 (d, J=7.58 Hz, 1 H), 8.08 (d, J=8.59 Hz, 2 H),8.24 (m, 2 H).

[0759] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 97% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.88 (q, J=6.91 Hz, 2 H), 3.04 (t, J=7.20 Hz, 2 H), 3.22(m, 2 H), 3.45 (m, 2 H), 5.25 (t, J=6.44 Hz, 1 H), 6.47 (d, J=9.09 Hz, 1H), 6.78 (dd, J=8.84, 2.02 Hz, 1 H), 6.84 (s, 1 H), 7.04 (dd, J=6.57,2.53 Hz, 4 H), 7.22 (d, J=2.02 Hz, 1 H), 7.31 (m, 7 H), 7.48 (d, J=3.79Hz, 2 H), 7.92 (d, J=7.83 Hz, 1 H), 8.12 (d, J=8.59 Hz, 2 H), 8.28 (d,J=8.34 Hz, 2 H).

EXAMPLE 2574-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0760] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 1,2-dimethylimidazole-4-sulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 80% yield. ¹HNMR (400 MHz, DMSO-D6) δ ppm 1.86 (m, 2 H), 2.18 (s, 3 H), 2.71 (m, 4H), 2.94 (m, 4 H), 3.49 (s, 3 H), 3.83 (s, 3 H), 6.42 (d, J=8.84 Hz, 1H), 6.76 (dd, J=8.84, 2.02 Hz, 1 H), 7.06 (m, 4 H), 7.36 (m, 8 H), 7.44(d, J=2.02 Hz, 1 H), 7.49 (s, 1 H), 7.59 (s, 1 H), 7.87 (d, J=8.08 Hz, 2H).

[0761] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 61% yield. ¹H NMR (400 MHz,DMSO-D6) δ ppm 1.87 (m, 2 H), 2.18 (s, 3 H), 2.70 (t, J=7.58 Hz, 4 H),2.95 (m, 4 H), 3.49 (s, 3 H), 6.42 (d, J=8.84 Hz, 1 H), 6.76 (dd,J=8.84, 2.02 Hz, 1 H), 7.06 (m, 5 H), 7.35 (m, 8 H), 7.44 (d, J=2.02 Hz,1 H), 7.49 (s, 1 H), 7.59 (t, J=4.93 Hz, 1 H), 7.85 (d, J=8.34 Hz, 2 H).HRMS: calcd for C₃₈H₃₇ClN₄O₄S, 680.2224; found (ESI+), 681.22879

EXAMPLE 2584-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0762] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 1,2-dimethylimidazole-4-sulfonyl chloride according to the procedurein Example 1, Step 7 in 84% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.25(s, 3 H), 3.07 (m, 2 H), 3.13 (m, 2 H), 3.18 (t, J=6.82 Hz, 2 H), 3.39(s, 3 H), 3.88 (s, 3 H), 4.17 (t, J=6.69 Hz, 2 H), 5.30 (m, J=2.78 Hz, 1H), 6.47 (d, J=9.09 Hz, 1 H), 6.79 (dd, J=8.84, 2.02 Hz, 1 H), 6.83 (d,J=8.84 Hz, 2 H), 6.93 (s, 1 H), 7.08 (m, 5 H), 7.29 (m, 6 H), 7.51 (d,J=2.02 Hz, 1 H), 7.94 (d, J=8.84 Hz, 2 H).

[0763] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 55% yield. ¹H NMR (400 MHz,DMSO-D6) δ ppm 2.17 (s, 3 H), 3.02 (m, J=9.10 Hz, 4 H), 3.14 (t, J=6.57Hz, 2 H), 3.47 (s, 3 H), 4.21 (t, J=6.69 Hz, 2 H), 6.47 (d, J=8.84 Hz, 1H), 6.79 (dd, J=8.84, 2.27 Hz, 1 H), 6.96 (d, J=8.84 Hz, 2 H), 7.07 (m,5 H), 7.36 (m, 6 H), 7.49 (s, 1 H), 7.63 (m, 2 H), 7.84 (d, J=8.84 Hz, 2H). HRMS: calcd. for C₃₇H₃₅ClN₄O₅S, 682.2017; found (ESI+), 683.20812.

EXAMPLE 2593-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl}propanoicacid

[0764] Step 1: This compound was prepared from3-(4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-phenyl)-propionicacid ethyl ester and 2-chlorosulfonyl chloride according to theprocedure in Example 1, Step 7 in 78% yield. ¹H NMR (400 MHz, CDCl₃) δppm 1.25 (m, 3 H), 2.66 (t, J=7.58 Hz, 2 H), 2.88 (q, J=6.48 Hz, 2 H),3.07 (m, 6 H), 3.34 (m, 2 H), 4.12 (q, J=7.07 Hz, 2 H), 5.31 (t, J=6.32Hz, 1 H), 6.45 (d, J=8.84 Hz, 1 H), 6.77 (dd, J=8.84, 2.02 Hz, 1 H),6.85 (s, 1 H), 7.04 (m, 4 H), 7.16 (d, J=1.77 Hz, 1 H), 7.30 (m, 7 H),7.46 (m, 4 H), 7.91 (m, 3 H).

[0765] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford, after flash chromatography, the title acid in41% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.74 (s, 4 H), 2.86 (t, J=6.69Hz, 2 H), 2.93 (m, 2 H), 3.08 (t, J=6.57 Hz, 2 H), 3.29 (m, 2 H), 6.43(d, J=8.84 Hz, 1 H), 6.61 (s, 1 H), 6.78 (m, 2 H), 7.00 (m, 4 H), 7.25(m, 7 H), 7.36 (d, J=1.77 Hz, 1 H), 7.45 (m, 2 H), 7.50 (d, J=8.34 Hz, 2H), 7.80 (d, J=7.58 Hz, 1 H), 7.93 (d, J=8.34 Hz, 2 H). HRMS: calcd. forC₄₀H₃₆Cl₂N₂O₆S₂(M−H) 773.1319 found 773.13107.

EXAMPLE 2604-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0766] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 3-chloro-4-methylbenzenesulfonyl chloride according to the procedurein Example 1, Step 7 in 100% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.38(s, 3 H), 2.92 (q, J=6.99 Hz, 2 H), 3.09 (t, J=7.58 Hz, 2 H), 3.18 (t,J=6.44 Hz, 2 H), 3.88 (s, 3 H), 4.21 (t, J=6.44 Hz, 2 H), 4.42 (t,J=6.44 Hz, 1 H), 6.54 (d, J=8.84 Hz, 1 H), 6.79 (m, 2 H), 6.83 (dd,J=8.84, 2.02 Hz, 1 H), 6.88 (s, 1 H), 7.04 (m, 4 H), 7.20 (d, J=8.08 Hz,1 H), 7.29 (m, 6 H), 7.40 (dd, J=7.96, 1.89 Hz, 1 H), 7.52 (d, J=2.02Hz, 1 H), 7.66 (d, J=1.77 Hz, 1 H), 7.93 (m, 2 H).

[0767] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1. The crude product was purified using flash chromatographyto afford the title acid in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm2.38 (s, 3 H), 2.93 (m, 2 H), 3.10 (t, J=7.45 Hz, 2 H), 3.19 (t, J=6.44Hz, 2 H), 4.23 (t, J=6.44 Hz, 2 H), 4.52 (s, 1 H), 6.54 (d, J=8.84 Hz, 1H), 6.83 (m, 3 H), 6.89 (s, 1 H), 7.04 (m, 4 H), 7.20 (d, J=8.08 Hz, 1H), 7.29 (m, 6 H), 7.40 (dd, J=8.08, 1.77 Hz, 1 H), 7.53 (d, J=2.02 Hz,1 H), 7.67 (d, J=2.02 Hz, 1 H), 7.98 (d, J=8.84 Hz, 2 H). HRMS: calcd.for C₃₉H₃₄Cl₂N₂O₅S, 712.1565; found (ESI+), 713.16268. Anal. Calcd forC₃₉H₃₄Cl₂N₂O₅S: C, 65.64; H, 4.80; N, 3.93. Found: C, 65.62; H, 4.52; N,3.73.

EXAMPLE 2614-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0768] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 3-chloro-4-methylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 98% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.95 (m, 2 H), 2.40 (s, 3 H), 2.72 (q, J=8.25Hz, 4 H), 2.82 (q, J=6.74 Hz, 2 H), 2.96 (t, J=7.33 Hz, 2 H), 3.91 (s, 3H), 4.27 (t, J=6.44 Hz, 1 H), 6.49 (d, J=8.84 Hz, 1 H), 6.80 (dd,J=8.97, 2.15 Hz, 1 H), 6.82 (s,1 H), 7.02 (m, 4 H), 7.26 (m, 9 H), 7.38(dd, J=7.96, 1.89 Hz, 1 H), 7.40 (d, J=2.02 Hz, 1 H), 7.66 (d, J=1.77Hz, 1 H), 7.96 (d, J=8.34 Hz, 2 H).

[0769] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford, after flash chromatography, the title acid in40% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.96 (m, 2 H), 2.40 (s, 3 H),2.73 (m, 4 H), 2.83 (m, 2 H), 2.98 (t, J=7.33 Hz, 2 H), 4.33 (t, J=6.32Hz, 1 H), 6.49 (d, J=8.84 Hz, 1 H), 6.80 (dd, J=8.84, 2.27 Hz, 1 H),6.83 (s, 1 H), 7.02 (m, 4 H), 7.21 (d, J=7.83 Hz, 1 H), 7.29 (m, 8 H),7.39 (m, 2 H),7.66 (d, J=1.77 Hz, 1 H), 8.00 (d, J=8.08 Hz, 2 H). HMRS:calcd. for C₄₀H₃₆Cl₂N₂O₄S, 710.1773; found (ESI+), 711.18411. Anal.Calcd for C₄₀H₃₆Cl₂N₂O₄S: C, 67.51; H, 5.10; N, 3.94. Found: C, 67.67;H, 5.27; N, 3.81.

EXAMPLE 2624-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0770] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 3-chloro-5-fluoro-2-methylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 in 100% yield. ¹H NMR (400 MHz, CDCl₃) δppm 2.26 (s, 3 H), 2.99 (m, 2 H), 3.10 (m, 2 H), 3.18 (t, J=6.57 Hz, 2H), 3.88 (s, 3 H), 4.21 (t, J=6.57 Hz, 2 H), 4.71 (t, J=6.32 Hz, 1 H),6.52 (d, J=8.84 Hz, 1 H), 6.81 (m, 3 H), 6.88 (s, 1 H), 7.04 (m, 4 H),7.14 (d, J=9.60 Hz, 1 H), 7.29 (m, 6 H), 7.52 (d, J=2.02 Hz, 1 H), 7.58(d, J=7.58 Hz, 1 H), 7.94(m,2H).

[0771] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 69% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.26 (s, 3 H), 2.99 (m, 2 H), 3.11 (m, 2 H), 3.19 (t,J=6.44 Hz, 2 H), 4.23 (t, J=6.44 Hz, 2 H), 4.79 (t, J=6.32 Hz, 1 H),6.52 (d, J=8.84 Hz, 1 H), 6.83 (m, 3 H), 6.88 (s, 1 H), 7.04 (m, 4 H),7.15 (d, J=9.60 Hz, 1 H), 7.29 (m, 6 H), 7.52 (d, J=2.02 Hz, 1 H), 7.59(d, J=7.58 Hz, 1 H), 7.99 (d, J=8.84 Hz, 2 H). HRMS: calcd. forC₃₉H₃₃Cl₂FN₂O₅S, 730.1471; found (ESI+), 731.1532.

EXAMPLE 2634-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0772] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoateadded and 3-chloro-5-fluoro-2-methylbenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to generate the product in 75%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.95 (m, 2 H), 2.27 (s, 3 H), 2.72(q, J=7.58 Hz, 4 H), 2.89 (t, J=6.82 Hz, 2 H), 2.97 (m, 2 H), 3.91 (s, 3H), 4.59 (t, J=6.19 Hz, 1 H), 6.47 (d, J=8.84 Hz, 1 H), 6.80 (dd,J=8.97, 2.15 Hz, 1 H), 6.82 (s, 1 H), 7.03 (dd, J=6.82, 2.53 Hz, 4 H),7.13 (d, J=9.60 Hz, 1 H), 7.24 (d, J=8.34 Hz, 2 H), 7.29 (m, 6 H), 7.40(d, J=2.02 Hz, 1 H) 7.58 (d, J=7.58 Hz, 1 H), 7.96 (d, J=8.34 Hz, 2 H).

[0773] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 96% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.96 (m, 2 H), 2.28 (s, 3 H), 2.74 (m,4 H), 2.89 (m, 2 H),2.99 (m, 2 H), 4.65 (q, J=6.32 Hz, 1 H), 6.47 (d, J=8.84 Hz, 1 H), 6.80(dd, J=8.97, 2.15 Hz, 1 H), 6.82 (s, 1 H), 7.03 (m, 4 H), 7.14 (d,J=9.60 Hz, 1 H), 7.30 (m, 8 H), 7.40 (d, J=2.02 Hz, 1 H), 7.58 (d,J=7.58 Hz, 1 H), 8.01 (d, J=8.08 Hz, 2 H) HMRS: calcd. forC₄₀H₃₅Cl₂FN₂O₄S, 728.1679; found (ESI+), 729.17441. Anal. Calcd forC₄₀H₃₅Cl₂FN₂O₄S: C, 65.84; H, 4.83; N, 3.84. Found: C, 65.49;, H, 5.02;N, 3.72.

EXAMPLE 2644-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0774] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 1) was added and 2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1, Step 7 to generate the productin 74% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.97 (m, 2 H), 2.73 (q,J=8.08 Hz, 4 H), 2.91 (m, 2 H), 3.04 (m, 2 H), 3.91 (s, 3 H), 5.33 (t,J=6.06 Hz, 1 H), 6.52 (d, J=8.84 Hz, 1 H), 6.80 (dd, J=8.84, 2.02 Hz,1H), 6.90 (s, 1 H), 7.06 (dd, J=6.57, 2.53 Hz, 4 H), 7.24 (d, J=8.34 Hz,2 H), 7.29 (m, 6 H), 7.39 (d, J=2.02 Hz, 1 H), 7.50 (td, J=7.71, 1.26Hz, 1 H), 7.65 (td, J=7.77, 1.39 Hz, 1 H), 7.75 (dd, J=7.83, 1.26 Hz, 1H), 7.80 (dd, J=7.96, 1.14 Hz, 1 H), 7.96 (d, J=8.08 Hz, 2 H).

[0775] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 100% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.98 (m, 2 H), 2.75 (m, 4 H), 2.92 (m, 2 H), 3.06 (m, 2 H),5.35 (t, J=6.06 Hz, 1 H), 6.52 (d, J=8.84 Hz, 1 H), 6.81 (dd, J=8.84,2.02 Hz, 1 H), 6.91 (s, 1 H), 7.07 (dd, J=6.82, 2.53 Hz, 4 H), 7.29 (m,8 H), 7.40 (d, J=2.02 Hz, 1 H), 7.51 (m, 1 H), 7.66 (m, 1 H), 7.76 (dd,J=7.83, 1.26 Hz, 1 H), 7.81 (dd, J=7.96, 1.14 Hz, 1 H), 8.01 (d, J=8.34Hz, 2 H) HMRS: calcd for C₃₉H₃₄ClN₃O₆S, 707.18568; found (ESI+),708.19296.

EXAMPLE 2654-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0776] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-nitrosulfonyl chloride according to the procedure in Example 1,Step 7 in 63% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.99 (m, 2 H), 3.19(m, 4 H), 3.88 (s, 3 H), 4.21 (t, J=6.57 Hz, 2 H), 5.40 (t, J=6.19 Hz, 1H), 6.57 (d, J=8.84 Hz, 1 H), 6.82 (m, 3 H), 6.96 (s, 1 H), 7.08 (m, 4H), 7.29 (m, 6 H), 7.49 (td, J=7.71, 1.26 Hz, 1 H), 7.52 (d, J=1.77 Hz,1 H), 7.65 (td, J=7.71, 1.26 Hz, 1 H), 7.80 (m, 2 H), 7.93 (d, 2 H).

[0777] Step 2: The ester intermediate was hydrolyzed according to Step8,Example 1 to afford the title acid in 90% yield. 1H NMR (400 MHz,CDCl₃) δ ppm 2.99 (m, 2 H), 3.20 (m, 4 H), 4.23 (t, J=6.57 Hz, 2 H),5.40 (t, J=6.19 Hz, 1 H), 6.57 (d, J=8.84 Hz, 1 H), 6.84 (m, 3 H), 6.95(s, 1 H), 7.08 (m, J=5.68, 3.66 Hz, 4 H), 7.29 (m, 6 H), 7.50 (m, 2 H),7.65 (td, J=7.77, 1.39 Hz, 1 H), 7.80 (m, 2 H), 7.98 (d, 2 H). HRMS:calcd for C₃₈H₃₂ClN₃O₇S, 709.16495; found (ESI+), 710.17059.

EXAMPLE 2664-[2-(1-benzhydryl-5-chloro-2-{2-[(mesitylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0778] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-mestitylenesulfonyl chloride according to the procedure in Example1, Step 7 in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.24 (s, 3 H),2.48 (s, 6 H), 2.90 (m, 2 H), 3.05 (m, 2 H), 3.16 (t, J=6.69 Hz, 2 H),3.89 (s, 3 H), 4.17 (t, J=6.69 Hz, 2 H), 4.48 (t, J=6.44 Hz, 1H), 6.52(d, J=8.84 Hz, 1 H)

[0779] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 68% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.24 (s, 3 H), 2.48 (s, 6 H), 2.90 (q, J=6.99 Hz, 2 H),3.06 (m, 2 H), 3.17 (t, J=6.69 Hz, 2 H), 4.19 (t, J=6.57 Hz, 2 H), 4.59(s, 1 H), 6.52 (d, J=8.84 Hz, 1 H), 6.82 (m, 6 H), 7.02 (m, 4 H), 7.29(m, 6 H), 7.52 (d, J=2.02 Hz, 1 H), 7.98 (d, J=8.84 Hz, 2 H). HRMS:calcd. for C₄₁H₃₉ClN₂O₅S, 706.22682; found (ESI+), 707.23370.

EXAMPLE 2674-(3-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trimethyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

[0780] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 1) was added 2-mesitylenebenzenesulfonyl chlorideaccording to the procedure in Example 1, Step 7 to generate the productin 83% yield. ¹H NMR (400 MHz, CHLOROF CDCl₃) δ ppm 1.93 (m, 2 H), 2.26(s, 3 H), 2.47 (s, 6 H), 2.70 (m, 4 H), 2.82 (m, 2 H), 2.91 (m, 2 H),3.91 (s, 3 H), 4.36 (t, J=6.44 Hz, 1 H), 6.46 (d, J=8.84 Hz, 1 H), 6.75(s, 1 H), 6.79 (dd, J=8.84, 2.27 Hz, 1 H), 6.88 (s, 2 H), 7.00 (m, 4 H),7.22 (d, J=8.34 Hz, 2 H), 7.28 (m, 6 H), 7.39 (d, J=2.02 Hz, 1 H), 7.95(d, J=8.34 Hz, 2 H).

[0781] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 84% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.94 (m, 2 H), 2.26 (s, 3 H), 2.47 (s, 6 H), 2.71 (m, 4 H),2.83 (m, 2 H), 2.93 (m, 2 H), 4.45 (t, J=5.81 Hz, 1 H), 6.46 (d, J=8.84Hz, 1 H), 6.75 (s, 1 H), 6.79 (dd, J=8.97, 2.15 Hz, 1 H), 6.88 (s, 2 H),7.00 (m, 4 H), 7.27 (m, 8 H), 7.40 (d, J=2.02 Hz, 1 H), 8.01 (d, J=8.34Hz, 2 H). HMRS: calcd. for C₄₂H₄₁ClN₂O₄S, 704.24756; found (ESI+),705.25452.

EXAMPLE 2684-(3-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

[0782] Step 1: 2-bromo-1-fluoro-3-trifluoromethylbenzene (1.0 eq.) wastaken up in tetrahydrofuran (0.5 M) and diethyl ether (0.5 M) and cooledto −78° C. nbutyllithium (2.5M, 1.0 eq.) was added dropwise and thereaction stirred for 40 minutes. A volume of sulfur dioxide equal to thevolume of THF was condensed and diluted with two volumes of ether. Thelithium salt of the benzene was canulated into the sulfur dioxide andthe reaction was allowed to slowly warm to room temperature. The solventwas removed and the resulting salt was washed with ether then taken upin hexanes (1.0M) and cooled in and ice bath. Sulfuryl chloride (1.06eq.) was added and the reaction warmed to room temperature and stirredfor 5 hours. The solvent was removed to give2-fluoro-6-trifluoromethylbenznesulfonyl chloride as a white, oily solidin 65% yield. The product was used crude. ¹H NMR (400 MHz, DMSO-D6) □ppm 7.46 (m, 1 H), 7.52 (m, 2 H).

[0783] Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to generate the product in 62%yield. 1H NMR (400 MHz, CDCl₃) □ ppm 1.94 (m, 2 H), 2.73 (m, 4 H), 2.91(m, 2 H), 2.99 (m, 2 H), 3.91 (s, 3 H), 4.87 (t, J=5.81 Hz, 1 H), 6.50(d, J=8.84 Hz, 1 H), 6.81 (dd, J=8.97, 2.15 Hz, 2 H), 7.03 (m, 4 H),7.24 (d, J=8.34 Hz, 2 H), 7.30 (m, 7 H), 7.41 (d, J=2.02 Hz, 1 H), 7.62(m, 2 H), 7.95 (d, J=8.34 Hz, 2 H).

[0784] Step 3: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 56% yield. ¹H NMR (400 MHz,CDCl₃) □ ppm 1.96 (m, 2 H), 2.75 (m, 4 H), 2.92 (m, 2 H), 3.00 (m, 2 H),4.93 (t, J=5.94 Hz, 1 H), 6.51 (d, J=8.84 Hz, 1 H), 6.82 (m, 2 H), 7.03(m, 4 H), 7.28 (m, 8 H), 7.32 (d, J=10.61 Hz, 1 H), 7.41 (d, J=2.02 Hz,1 H,) 7.63 (m, 2 H), 8.01 (d, J=8.08 Hz, 2 H). HRMS calc for[C₄₀H₃₃ClF₄N₂O₄S+H] 749.18585 found 749.18578.

EXAMPLE 2694-(2-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

[0785] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to afford product in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.00 (m, 2 H), 3.12 (m, 2 H), 3.20 (t,J=6.44 Hz, 2 H), 3.88 (s, 3 H), 4.20 (t, J=6.44 Hz, 2 H), 4.99 (t,J=6.06 Hz, 1 H), 6.54 (d, J=8.84 Hz, 1 H), 6.79 (d, J=8.84 Hz, 2 H),6.84 (dd, J=8.97, 2.15 Hz, 1 H), 6.88 (s, 1 H), 7.04 (dd, J=6.82, 2.53Hz, 4 H), 7.28 (m, 6 H), 7.33 (m, 1 H), 7.54 (d, J=2.02 Hz, 1 H), 7.60(m, 2 H), 7.93 (d, J=9.10 Hz, 2 H).

[0786] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 36% yield. ¹H NMR (400 MHz,CDCl₃) □ ppm 3.01 (m, 2 H), 3.13 (m, 2 H), 3.21 (t, J=6.44 Hz, 2 H),4.22 (t, J=6.44 Hz, 2 H), 5.07 (t, J=6.06 Hz, 1 H), 6.55 (d, J=8.84 Hz,1 H), 6.83 (m, 3 H), 6.88 (s, 1 H), 7.04 (m, 4 H), 7.28 (m, 6 H), 7.32(m, 1 H), 7.55 (d, J=2.02 Hz, 1 H), 7.61 (m, 2 H), 7.98 (d, J=8.84 mHz,2 H). HRMS calc for [C₃₉H₃₁ClF₄N₂O₅S+H] 751.16511 found 751.16431.

EXAMPLE 2704-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0787] Step 1: 2,6-Dimethylbenzenesulfonyl chloride was prepared from2-bromo-1,3-dimethylbenzene according to the procedure in Example 18,Step 1-2. The reaction gave product as a white solid in 84% yield. ¹HNMR (400 MHz, DMSO-D6) □ ppm 2.54 (s, 6 H), 6.94 (d, J=7.33 Hz, 2 H),7.02 (m, 1 H).

[0788] Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-dimethylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 66% yield. ¹HNMR (400 MHz, CDCl₃) □ ppm 1.93 (m, 2 H), 2.50 (s, 6 H), 2.70 (m, 4 H),2.82 (m, 2 H), 2.93 (m, 2 H), 3.91 (s, 3 H), 4.40 (t, J=6.32 Hz, 1 H),6.47 (d, J=8.84 Hz, 1 H), 6.77 (s 1 H), 6.80 (dd, J=8.97, 2.15 Hz, 1 H),7.00 (m, 4 H), 7.07 (d, J=7.58 Hz, 2 H), 7.22 (d, J=8.08 Hz, 2 H), 7.27(m, 7 H), 7.40 (d, J=2.02 Hz, 1 H), 7.95 (d, J=8.08 Hz, 2 H).

[0789] Step 3: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 96% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.81 (m, 2 H,) 2.50 (s, 6 H), 2.65 (m, 4 H), 2.81 (m, 2H), 2.87 (m, 2 H), 6.45 (d, J=8.84 Hz, 1 H), 6.77 (dd, J=8.84, 2.27 Hz,1 H), 6.94 (s, 1 H), 7.02 (m, 4 H), 7.17 (d, J=7.58 Hz, 2 H), 7.28 (d,J=8.34 Hz, 2 H), 7.33 (m, 6 H), 7.43 (d, J=2.27 Hz, 1 H), 7.70 (t,J=5.81 Hz, 1 H), 7.85 (d, J=8.08 Hz, 2 H). HRMS calc for[C₄₁H₃₉ClN₂O₄S+H] 691.23919 found 691.23872.

EXAMPLE 2714-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0790] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-dimethylbenzenesulfonyl chloride (Example 266, Step 1)according to the procedure in Example 1, Step 7 to afford product in 88%yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 2.51 (s, 6 H), 2.90 (m, 2 H), 3.06(m, 2 H), 3.16 (t, J=6.69 Hz, 2 H), 3.89 (s, 3 H), 4.17 (t, J=6.57 Hz, 2H), 4.50 (t, J=6.19 Hz, 1 H), 6.53 (d, J=8.84 Hz, 1 H), 6.79 (d, J=9.10Hz, 2 H), 6.83 (m, 2 H), 7.02 (m, 4 H), 7.06 (d, J=7.58 Hz, 2 H), 7.23(m, 1 H), 7.28 (m, 6 H), 7.53 (d, J=2.02 Hz, 1 H), 7.93 (d, J=8.84 Hz, 2H).

[0791] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 79% yield. ¹H NMR (400 MHz,DMSO-D7) □ ppm 2.48 (s, 6 H), 2.85 (m, 2 H), 2.95 (m, 2 H),3.08 (t,J=6.57 Hz, 2 H), 4.15 (t, J=6.69 Hz, 2 H), 6.48 (d, J=8.84 Hz, 1 H),6.79 (dd, J=8.84, 1.77 Hz, 1 H), 6.90 (d, J=8.84 Hz, 2 H), 6.95 (s, 1H), 7.01 (m, 4 H), 7.14 (d, J=7.58 Hz, 2 H), 7.29 (m, 6 H), 7.63 (d,J=2.02 Hz, 1 H), 7.73 (t, J=5.94 Hz, 1 H), 7.82 (d, J=8.84 Hz, 2 H).HRMS calc for [C₄₀H₃₇ClN₂O₅S+H] 693.21845 found 693.21791.

EXAMPLE 2724-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0792] Step 1: 2,6-Diethylbenzenesulfonyl chloride was prepared from2-bromo-1,3-diethylbenzne according to the procedure in Example 18, Step1-2. The reaction gave product as a pale yellow, oily solid in 36%yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm 1.13 (t, J=7.33 Hz, 6 H), 3.08(q, J=7.33 Hz, 4 H), 6.96 (d, J=7.58 Hz, 2 H), 7.10 (m, 1 H).

[0793] Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-diethylbenzenesulfonyl chloride according to the procedurein Example 1, Step 7 to afford product in 72% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.10 (t, J=7.33 Hz, 6 H), 2.91 (m, 6 H), 2.99 (m, 2 H),3.11 (t, J=6.69 Hz, 2 H), 3.81 (s, 3 H), 4.18 (t, J=6.69 Hz, 2 H), 6.49(d, J=8.84 Hz, 1 H), 6.80 (dd, J=8.84, 2.02 Hz, 1 H), 6.93 (d, J=8.84Hz, 2 H), 6.97 (s, 1 H), 7.02 (m, 4 H), 7.17 (d, J=7.58 Hz, 2 H), 7.32(m, 5 H), 7.38 (t, J=7.71 Hz, 1 H), 7.65 (d, J=2.02 Hz, 1 H), 7.74 (t,J=5.94 Hz, 1 H), 7.85 (d, J=8.84 Hz, 2 H).

[0794] Step 3: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 88% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.10 (t, J=7.33 Hz, 6 H), 2.91 (m, 6 H), 2.98 (d, J=7.83Hz, 2 H), 3.10 (t, J=6.57 Hz, 2 H), 4.17 (t, J=6.69 Hz, 2 H), 6.49 (d,J=8.84 Hz, 1 H), 6.80 (dd, J=8.84, 2.02 Hz, 1 H), 6.91 (d, J=9.09 Hz, 2H), 6.97 (s, 1 H), 7.02 (m, 4 H), 7.17 (d, J=7.58 Hz, 2 H), 7.32 (m, 5H), 7.38 (t, J=7.58 Hz, 1 H), 7.65 (d, J=2.27 Hz, 1 H), 7.74 (t, J=5.81Hz, 1 H), 7.83 (d, J=8.84 Hz, 2 H). HRMS calc for [C₄₂H₄₁ClN₂O₅S+H]721.24975 found 721.24876.

EXAMPLE 2734-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0795] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-diethylbenzenesulfonyl chloride (Example 268, Step 1)according to the procedure in Example 1, Step 7 to generate the productin 71% yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm 1.11 (t, J=7.33 Hz, 6 H),1.81 (m, 2 H), 2.65 (m, 4 H), 2.84 (m, 2 H), 2.90 (m, 6 H), 3.84 (s, 3H), 6.44 (d, J=8.84 Hz, 1 H), 6.77 (dd, J=8.84, 2.02 Hz, 1 H), 6.94 (s,1 H), 7.02 (m, 4 H), 7.19 (d, J=7.58 Hz, 2 H), 7.33 (m, 7 H), 7.40 (t,J=7.71 Hz, 1 H), 7.43 (d, J=2.02 Hz, 1 H), 7.70 (t, J=5.68 Hz, 1 H),7.86 (d, J=8.34 Hz, 2 H).

[0796] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 85% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.11 (t, J=7.33 Hz, 6 H), 1.81 (m, 2 H), 2.65 (m, 4 H),2.84 (m, 2 H), 2.91 (m, 6 H), 6.45 (d, J=8.84 Hz, 1 H), 6.77 (dd,J=8.84, 2.02 Hz, 1 H), 6.95 (s, 1 H), 7.02 (m, 4 H),7.19 (d, J=7.58 Hz,2 H), 7.28 (d, J=8.34 Hz, 2 H), 7.33 (m, 5 H), 7.40 (m, 1 H), 7.43 (d,J=2.27 Hz, 1 H), 7.70 (t, J=5.68 Hz, 1 H), 7.84 (d, J=8.34 Hz, 2 H).HRMS calc for [C₄₃H₄₃ClN₂O₄S+H] 719.27049 found 719.27028.

EXAMPLE 2744-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0797] Step 1: 1,3-dimethoxybenzene (1.0 eq). was taken up in diethyether (0.2M) and n-butyllithium (1.0 eq.) was added dropwise. Thereaction was heated to reflux for three hours. It was cooled to roomtemperature then it was placed in a dry ice acetone bath and cooled to−50° C. Bromide (0.98 eq.) was added and the reaction was allowed towarm slowly to room temperature. The reaction was quenched withsaturated sodium thiosulfate and the aqueous layer was extracted withether. The organic extracts were washed with brine, dried over sodiumsulfate and concetrated to give a brown solid. The solid wasrecrystalized from hexanes to give the product as a white solid in 27%yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm 3.83 (s, 6 H), 6.73 (d, J=8.34Hz, 2 H), 7.30 (t, J=8.34 Hz, 1 H).

[0798] Step 2: 2,6-Dimethoxybenzenesulfonyl chloride was prepared from2-bromo-1,3-dimethoxybenzne according to the procedure in Example 1,Step 1. The reaction gave a mixture of sulfonyl chloride and anotherproduct as a white solid.

[0799] Step 3. To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-dimethoxybenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to afford product in 72% yield. 1H NMR(400 MHz, CDCl₃) □ ppm 3.08 (m, 2 H), 3.14 (m, 2 H), 3.20 (t, J=6.69 Hz,2 H),3.64 (s, 6 H), 3.88 (s, 3 H), 4.18 (t, J=6.69 Hz, 2 H), 5.41 (t,J=5.68 Hz, 1 H), 6.42 (d, J=8.84 Hz, 1 H), 6.52 (d, J=8.59 Hz, 2 H),6.79 (m, 3 H), 6.91 (s, 1 H), 7.02 (m, 4 H), 7.25 (m, 6 H), 7.36 (t,J=8.46 Hz, 1 H, 7.54 (d, J=2.02 Hz, 1 H), 7.93 (d, J=8.84 Hz, 2 H). m/z(M−) 737.

[0800] Step 4. The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 100% yield. 1H NMR (400 MHz,CDCl₃) □ ppm 3.08 (m, 2 H), 3.15 (m, 2 H), 3.21 (t, J=6.69 Hz, 2 H),3.64 (s, 6 H), 4.20 (t, J=6.57 Hz, 2 H), 5.44 (m, 1 H), 6.42 (d, J=8.84Hz, 1 H), 6.53 (d, J=8.59 Hz, 2 H), 6.79 (dd, J =8.84, 2.02 Hz, 1 H),6.83 (d, J=8.84 Hz, 2 H), 6.91 (s, 1 H), 7.02 (m, 4 H), 7.25 (m, 6H),7.36 (t, J=8.46 Hz, 1 H), 7.54 (d, J=2.02 Hz, 1 H), 7.98 (d, J=8.84Hz, 2 H). HRMS calc for [C₄₀H₃₇ClN₂O₇S+H] 725.20729 found 719.27028.

EXAMPLE 2754-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0801] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-dimethoxybenzenesulfonyl chloride(Example 270, Step 1)according to the procedure in Example 1, Step 7 to generate the productin 80% yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 1.94 (m, 2 H), 2.72 (m, 4H), 3.01 (m, 4 H), 3.59 (s, 6 H), 3.91 (s, 3 H), 5.37 (m, 1 H), 6.37 (d,J=8.84 Hz, 1 H), 6.53 (d, J=8.59 Hz, 2 H), 6.76 (dd, J=8.97, 2.15 Hz, 1H), 6.84 (s, 1 H), 6.98 (m, 4 H), 7.21 (d, J=8.34 Hz, 2 H), 7.26 (m, 6H), 7.38 (m, 2 H), 7.94 (d, J=8.34 Hz, 2 H). m/z (M+737.

[0802] Step 2: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 91% yield. ¹H NMR (400 MHz,CDCl₃) □ ppm 1.95 (m, 2 H), 2.74 (m, 4 H), 3.02 (m, 4 H), 3.60 (s, 6 H),5.41 (s, 1 H), 6.37 (d, J=8.84 Hz, 1 H), 6.53 (d, J=8.59 Hz, 2 H), 6.76(dd, J=8.84, 2.27 Hz, 1 H), 6.84 (s, 1 H), 6.99 (m, 4 H), 7.25 (m, 8 H),7.37 (t, J=8.46 Hz, 1 H), 7.40 (d, J=2.02 Hz, 1 H), 7.99 (d, J=8.34 Hz,2 H). HRMS calc for [C₄₁H₃₉ClN₂O₆S+H] 723.22902 found 723.22893.

EXAMPLE 2764-{2-[1-Benzhydryl-5-nitro-2-(3-phenylmethanesulfonyl-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid

[0803] Step 1. 4-Nitroaniline (1.0 eq.) was taken up in water (0.8 M)and concetrated HCl (10.8 M). Iodine monochloride (1 eq.) was added to a4 to 1 solution of water and concetrated HCl (1.3 M) and cooled to 0° C.The ICl solution was added to the aniline solution and the reaction satat room temperature for 20 hours. The reaction was filtered to give theiodinated product as a yellow solid in 97.3% yield. ¹H NMR (300 MHz,DMSO-D6) δ ppm 6.75 (d, J=9.07 Hz, 1 H), 7.98 (dd, J=9.07, 2.47 Hz, 1H), 8.40 (d, J=2.47 Hz, 1 H). MS m/z 263 (M−H).

[0804] Step 2. To the 2-iodo-4-nitroaniline (1 eq.) andbenzhydrylbromide (1.3 eq were taken up in dichloroethane (0.8 M).Diisopropylethylamine (1.1 eq.) was added and the reaction heated to 50°C. for 20 hours. The reaction mixture was cooled and washed with 1 NHCl, dried over Na₂SO₄ and concentrated. Purifiction using flashchromatography (10% ethyl acetate in hexanes) gave the alkylated productin 81% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.56 (d, J=4.80 Hz, 1 H),5.67 (d, J=5.05 Hz, 1 H), 6.36 (d, J=9.10 Hz, 1 H), 7.32 (m, 6 H), 7.38(m, 4 H), 7.99 (dd, J=9.09, 2.53 Hz, 1 H) 8.61 (d, J=2.53 Hz, 1 H).

[0805] Step 3. Benzhydryl-(4-nitro-2-iodo-phenyl)-amine (1 eq.),4-(6-hydroxy-hex-3-ynyloxy)-benzoic acid methyl ester (1.5 eq.), LiCl (1eq.) KOAc (5 eq.) and palladium (II) acetate (0.04 eq.) were added to aroundbottom containing 10 mL of DMF that had been degassed with argon.The reaction heated to 100° C. 7.5 hours. It was then cooled, dilutedwith ethyl acetate, washed with water and brine, dried over Na₂SO₄ andconcentrated to give a brown solid. Purification by flash chromatographygave two products,4-{2-[1-benzhydryl-5-nitro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester and the desired,4-{2-[1-benzhydryl-5-nitro-3-(2-hydroxy-ethyl)-1H-indol-2-yl]-ethoxy}-benzoicacid methyl ester in an overall yield of 71%. The products were notseperable by flash chromatography and were both carried on to the nextstep. ¹H NMR (400 MHz, CDCl₃) □ ppm 1.66 (t, J=5.56 Hz, 1 H), 1.80 (t,J=5.18 Hz, 1 H), 3.14 (m, 4 H), 3.35 (m, 4 H), 3.81 (m, 2 H), 3.87 (m,J=1.52 Hz, 6 H), 3.97 (q, J=6.32 Hz, 2 H), 4.10 (t, J=6.82 Hz, 2 H),4.31 (t, J=6.19 Hz, 2 H), 6.58 (d, J=4.04 Hz, 1 H), 6.60 (d, J=4.04 Hz,1 H), 6.67 (d, J=9.10 Hz, 2 H), 6.89 (d, J=8.84 Hz, 2 H), 7.10 (m, 9 H),7.20 (s, 1 H), 7.32 (m, 12 H), 7.75 (m, 2 H), 7.90 (d, J=8.84 Hz, 2 H),7.95 (d, J=9.09 Hz, 2 H), 8.52 (d, J=2.27 Hz, 1H), 8.59 (d, J=2.27 Hz, 1H).

[0806] Step 4. The regiosiomers(1.0 eq.) from the previous step weretaken up in THF. Triethylamine (1.2 eq.) and methanesulfonyl chloride(1.2 eq.) were added. The reaction stirred until the starting materialwas consumed as monitored but TLC. The reaction was diluted withdichloromethane and washed with water and brine. It was dried overNa₂SO₄ and concentrated. The reaction gave an inseperable mixture ofisomers in 100% yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 2.81 (s, 3 H), 2.90(s, 3 H), 3.35 (m, 8 H), 3.87 (m, J=1.52 Hz, 6 H), 4.07 (t, J=6.19 Hz, 2H), 4.14 (t, J=7.20 Hz, 2 H), 4.30 (t, J=6.06 Hz, 2 H), 4.49 (t, J=6.69Hz, 2 H), 6.62 (d, J=6.57 Hz, 1 H), 6.65 (d, J=6.57 Hz, 1 H), 6.69 (d,J=8.84 Hz, 2 H), 6.88 (d, J=9.09 Hz, 2 H), 7.02 (s, 1 H), 7.10 (dd,J=7.71, 4.67 Hz, 8 H), 7.23 (s, 1 H), 7.34 (m, 12 H), 7.79 (m, 2 H),7.91 (d, J=8.84 Hz, 2 H), 7.96 (d, J=8.84 Hz, 2 H), 8.49 (d, J=2.27 Hz,1 H), 8.62 (d, J=2.02 Hz, 1 H).

[0807] Step 5. The mixture of crude mesylates (1 eq.) from above andsodium azide (2.2 eq.) were taken up in DMSO (0.05 M). The reactionstirred at room temperature until the starting material was consumed asmonitered by TLC. The reaction was diluted with ethyl acetate, washedwith water and brine, dried over Na₂SO₄ and concentrated to give thedesired azides in quantitative yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 3.12(m, 4 H), 3.33 (m, 6 H), 3.64 (t, J=6.82 Hz, 2 H), 3.88 (m, J=1.52 Hz, 6H), 4.05 (t, J=6.32 Hz, 2 H), 4.29 (t, J=6.19 Hz, 2 H), 6.65 (m, 4 H),6.87 (d, J=8.84 Hz, 2 H), 7.02 (s, 1 H), 7.10 (m, 8 H), 7.21 (s, 1 H),7.34 (m, 12 H), 7.78 (m, 2 H), 7.91 (d, J=8.84 Hz, 2 H), 7.96 (d, J=8.84Hz, 2 H), 8.49 (d, J=2.27 Hz, 1 H), 8.61 (d, J=2.27 Hz, 1 H).

[0808] Step 6. The mixture of inseperable azides (1.0 eq.) from Step 5and triphenylphosphine (1.1 eq.) were taken up in THF and stirred atroom temperature until the starting material was consumed giving aproduct with a higher Rf by TLC. 1 ml of water was added to the reactionand it continued to stir at room temperature until TLC showed thedisapperance of the higher Rf intermediate. The THF was removed in vacuoand the resulting solid was taken up in ethyl acetate, washed with waterand brine, dried over Na₂SO₄ and concentrated. Purification by flashchromatography gave 43% overall yield of reduced products. Theregioisomers where separated using flash chromatography (gradientelution 0.25% methanol in dichloromethane to 10% methanol indichloromethane.) The regioisomers were identified by NMR and thedesired compound,4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester, was taken on to the next step. 1H NMR (400 MHz,CDCl₃) δ ppm 3.30 (m, 6 H), 3.88 (s, 3 H), 4.27 (t, J=6.57 Hz, 2 H),6.56 (d, J=9.35 Hz, 1 H), 6.88 (d, J=9.10 Hz, 2 H), 7.10 (dd, J=6.44,2.65 Hz, 4 H), 7.32 (m, 7 H), 7.72 (dd, J=9.09, 2.27 Hz, 1 H), 7.95 (d,J=8.84 Hz, 2 H), 8.60 (d, J=2.27 Hz, 1 H). MS m/z 550 (M+).

[0809] Step 7. To4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was added α-toluenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 61% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.89 (m, 2 H) 3.09 (m, 2 H), 3.25 (t, J=6.06Hz, 2 H), 3.88 (s, 3 H), 4.09 (s, 2 H), 4.15 (m, 1 H), 4.25 (t, J=6.06Hz, 2 H), 6.61 (d, J=9.35 Hz, 1 H), 6.84 (d, J=8.84 Hz, 2 H), 6.97 (s, 1H), 7.07 (m, 4 H),7.20 (m, J=8.08, 1.52 Hz, 2 H),7.32 (m, 9 H), 7.77(dd, J=9.10, 2.27 Hz, 1 H), 7.95 (d, J=9.10 Hz, 2 H), 8.59 (d, J=2.27Hz, 1 H). MS m/z 703 (M−H).

[0810] Step 8: The ester intermediate was hydrolyzed according to Step8, Example 1 to afford the title acid in 75% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.90 (m, 2 H), 3.10 (m, 2 H), 3.26 (t, J=6.06 Hz, 2 H),4.10 (s, 2 H), 4.26 (t, J=6.06 Hz, 2 H), 4.37 (t, J=6.19 Hz, 1 H), 6.61(d, J=9.35 Hz, 1 H), 6.85 (d, J=9.09 Hz, 2 H), 6.97 (s, 1 H), 7.07 (m, 4H), 7.20 (m, 2 H), 7.32 (m, 9 H), 7.76 (dd, J=9.10, 2.27 Hz, 1 H), 7.97(d, J=8.84 Hz, 2 H), 8.58 (d, J=2.27 Hz, 1 H). HRMS: calcd. forC₃₉H₃₅N₃O₇S, 689.2196; found (ESI+) 690.22581.

EXAMPLE 2774-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-(2-chloro-1-methylethyl)benzene}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0811] Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and2-(2-chloro-1-methylethyl)benzenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 65% yield.

[0812] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₄₀Cl₂N₂O₄S+H] 739.21586 found 739.21611.

EXAMPLE 2784-[2-(1-Benzhydryl-2-{2-[(2-(2-chloro-1-methylethyl)benzene)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

[0813] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-(2-chloro-1-methylethyl)benzenesulfonylchloride according to the procedure in Example 1 Step 7 in 61% yield.

[0814] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. m/z (M−1)=739.3

EXAMPLE 2794-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0815] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-dimethylbenzylsulfonyl chloride according tothe procedure in Example 1 Step 7 in 45% yield.

[0816] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield. m/z (M−1)=738.2

EXAMPLE 2804-[3-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]-ethyl}-1H-indol-3-yl)propyl]benzoicacid

[0817] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and cyclopropanesulfonyl chloride according to theprocedure in Example 1 Step 7 in 83% yield.

[0818] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 80% yield. HRMS calc forC₃₆H₃₅ClN₂O₄S, 626.2006; found (ESI+), 627.20734.

EXAMPLE 2814-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0819] Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and □-phenylethanesulfonyl chloride(prepared following a procedure in J. Org. Chem. 1984, 49, 5124-5131)according to the procedure in Example 1 Step 7 to generate the productin 77% yield.

[0820] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc forC₄₁H₃₉ClN₂O₄S, 690.2313; found (ESI+), 691.2383.

EXAMPLE 2824-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0821] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and □-phenylethanesulfonyl chloride according to theprocedure in Example 1 Step 7 in 81% yield.

[0822] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calcd forC₄₀H₃₇ClN₂O₅S, 692.2115; found (ESI+), 693.2185.

EXAMPLE 2832-{2-[1-Benzhydryl-5-chloro-2-(2-phenylmethanesulfonyl-amino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid

[0823] Step 1: Crude2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanolfrom step 6, example 142 was treated with 3-Hydroxy-benzoic acid methylester according to the procedure in Example 142 step 8 to yield thedesired3-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 85% yield.

[0824] Step 2: The deprotected compound was prepared according to theprocedure described for Example 142 step 9. The crude3-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was used in the next step directly without furtherpurification.

[0825] Step 3-5:3-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was prepared according to the procedure described forexample 146 steps 3-7 in 57% (3 steps).

[0826] Step 6: To3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was added □-toluenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 73% yield.

[0827] Step 7: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.2029.

EXAMPLE 2842-(2-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichlorophenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0828] Step 1: To3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 5, Example 279) was added3,4-dichlorophenylmethanesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 84% yield.

[0829] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+H] 747.12486 found 747.12423.

EXAMPLE 2853-{2-[1-Benzhydryl-5-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid

[0830] Step 1: Crude2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanolfrom step 6, example 142 was treated with 2-Hydroxy-benzoic acid methylester according to the procedure in Example 142 step 8 to yield thedesired2-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 60% yield.

[0831] Step 2: The deprotected compound was prepared according to theprocedure described for Example 142 step 9. The crude2-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was used in the next step directly without furtherpurification.

[0832] Step 3-5:2-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was prepared according to the procedure described forexample 146 steps 3-7 in 60% (3 steps).

[0833] Step 6: To2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy)-benzoicacid methyl esterwas added □-toluenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 90% yield.

[0834] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.20358.

EXAMPLE 2863-(2-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

[0835] Step 1: To2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy)-benzoicacid methyl ester (Step 5, Example 281) was added3,4-dichlorophenylmethanesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 84% yield.

[0836] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+H] 747.12486 found 747.12457.

EXAMPLE 2874-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0837] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step1, was added 2,4-dichlorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 50% yield.

[0838] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1)776.92.

EXAMPLE 2884-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-difluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0839] Step1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step1, was added 2,4-difluorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 27% yield.

[0840] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1)744.97.

EXAMPLE 2894-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

[0841] Step1: The methyl4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate(Step 1 Example 219) in THF was oxidized with mCPBA (1.1 equiv.) Thecrude was purified by the flash column with 30% EtOAc/hexane in 42%yield.

[0842] Step2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. m/z (M−1)795.14.

EXAMPLE 2904-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-hydroxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0843] Step 1:4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-penta-2,4-dienyloxy)-benzenesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid (0.55 g, 0.70 mmole), (Step 1, Example 183) and 10% Pd/C (55 mg) inMeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixturewas filtered through Celite and concentrated. The residue waschromatographed with 35-40% EtOAC/hexane to give the desired product(0.50 g, 95%).

[0844] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS: calcd forC₃₈H₃₃ClN₂O₆S, 680.1748; found (ESI+), 681.18118

EXAMPLE 291N-{2-[1-benzhydryl-5-chloro-3-(2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}ethyl)-1H-indol-2-yl]ethyl}-1-(3,4-dichlorophenyl)methanesulfonamide

[0845] Step 1: The2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142) was coupled with 4-Hydroxy-benzaldehyde accordingto the conditions described in Example 189, Step 1 to yield4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzaldehydein 70% yield.

[0846] Step 2: The silyl ether from above was deprotected following theExample 142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1#H!-indol-3-yl]-ethoxy}-benzaldehydein 90% yield.

[0847] Step 3: The alcohol from above was activated by conversion to themesylate as described in Step 10 Example 142 to yield the desiredmesylate which was used without purification in the next step.

[0848] Step 4: The mesylate from above was treated under the conditionsdescribed in Step 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehydein 98% yield (2 steps).

[0849] Step 5: The mixture of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehyde(1.29 g, 2.41 mmole, 1.0 equiv.), 2,4-thiazolidine dione (0.41 g, 3.13mmole, 1.3 equiv.) and piperidine (0.12 ml, 1.21 mmole, 0.5 equiv.) inEtOH (125 ml) was refluxed overnight. EtOH was removed on vacuo. Theresidue was diluted in EtOAc and washed with water, then brine. Theorganic layer was dried over MgSO₄ and concentrated, and the residue waschromatographed with 30-35% EtOAc/hexane to obtain5-(4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione(1.33 g, 87%).

[0850] Step 6: To a solution of the product from step 5 in THF (80 ml)was added Ph₃P in small portions. The mixture was stirred for 1 day. 3ml of water was added, and stirred for an additional 2 days. Theproduced solid, which was identified as triphenyl phosphine imine of theabove azide.(60%) by LC/MS, was filtered.

[0851] Step 7: The imine (250 mg, 0.29 mmole, 1.0 equiv.) from step 6,and (3,4-dichlorophenyl)methylsulfonyl chloride in CH₂Cl₂ (10 ml) andsaturated NaHCO₃ (5 ml) was stirred overnight according to the procedurein Example 1 Step 7 to generate the product in 7% yield. m/z (M−1)830.45

EXAMPLE 292N-[2-(1-Benzhydryl-5-chloro-3-{2-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-ethyl}-1H-indol-2-yl)-ethyl]-2-methyl-benzenesulfonamide

[0852] Step 1: The mixture of triphenylphosphine imine (300 mg, 0.35mmole, 1.0 equiv.) from Step 6, Example 287 and 2-methyl-benzenesulfonylchloride in CH₂Cl₂ (15 ml) and saturated NaHCO₃ (5 ml) was stirredovernight according to the procedure in Example 1 Step 7 to generate theproduct in 3% yield. HRMS calc for [C₄₂H₃₆ClN₃O₅S −H] 760.1723 found760.1728.

EXAMPLE 2934-{3-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0853] Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 1-Methyl-1H-imidazole-2-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 70% yield.

[0854] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₇H₃₅ClN₄O₄S+H] 667.2141 found 667.2137.

EXAMPLE 2944-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

[0855] Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 1-Methyl-1H-imidazole-2-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 76% yield.

[0856] Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 87% yield. HRMS calc for[C₃₆H.₃₃ClN₄O₅.S+H] 669.1933 found 669.1933.

EXAMPLE 2954-{3-[1-benzhydryl-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

[0857] Step 1: A mixture of methyl-4-iodobenzoate (5.3 g, 20.2 mmol),allyl alcohol (1.78 g, 30.3 mmol), NaHCO₃ (4.24 g, 50.5 mmol), Pd(OAc)₂(0.14 g, 0.60 mmol), (n-Bu)₄NBr (6.55 g, 20.2 mmol) and 4-A molecularSieves (4.1 g) in anhydrous DMF (69 mL) was stirred at room temperaturefor 4 days. The reaction mixture was filtered through celite and thefiltrate poured onto water and extracted with EtOAc. Organic layer waswashed with brine, dried (Na₂SO₄), and concentrated under vacuum. Flashchromatography (silica gel, 10-20% EtOAc-hexanes) gave 2.11 g (85% basedon the recovered starting material) of the desired4-(3-Oxo-propyl)-benzoic acid methyl ester as a clear oil.

[0858] Step 2: To a solution of 2-Methyl-1H-indole (0.86 g, 5.2 mmol)and 4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) inmethylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followedby triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirredovernight, quenched with sat. NaHCO₃ solution (50 mL), and the organiclayer was washed with sat. NaHCO₃ solution, water, brine, and dried(Na₂SO₄). Solvent was removed under reduced pressure, and the residuewas purified by flash column chromatography with 10-20% EtOAc/hexanes toyield the desired 4-[3-(2-Methyl-1H-indol-3-yl)-propyl]-benzoic acidmethyl ester in 88% (1.67 g) yield.

[0859] Step 3: To a solution of the product from step 2 (1.66 g, 4.86mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83mmol) under N₂ atmosphere. The mixture was stirred for 1 h at roomtemperature, followed by the dropwise addition of benzhydryl bromide(1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirredovernight at room temperature. Water (500 mL) was added to reactionmixture, it was extracted with EtOAc, washed with brine, dried (Na₂SO₄),and concentrated under reduced pressure to a brown syrup, which waspurified by silica-gel chromatography using 10% EtOAc/hexanes as eluentto isolate 4-[3-(1-Benzhydryl-2-methyl-1H-indol-3-yl)-propyl]-benzoicacid methyl ester as a white solid in 76% (1.47 g) yield.

[0860] Step 4: The product from above (1.46 g, 2.87 mmol) was dissolvedin CCl₄ (14.5 mL), followed by the addition of NBS (1.02 g, 5.73 mmol)and benzoyl peroxide (2 mg). The reaction mixture was heated to refluxfor 1 h (until all the starting material disappeared). This mixture wascooled to room temperature, filtered and the solid was washed with CCl₄.The filtrate was evaporated to a brown residue, which was dissolved inacetone (40 mL) and water (4 mL), Ag₂CO₃ (1.75 g, 3.16 mmol) was thenadded to this solution and after being stirred overnight at roomtemperature, it was filtered through celite, the solvent was evaporatedunder reduced pressure, and water was added to the residue. It wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), and evaporatedto a syrup, which was purified by 10% EtOAc/hexanes to isolate the4-[3-(1-Benzhydryl-2-formyl-1H-indol-3-yl)-propyl]-benzoic acid methylester (1.13 g) in 85% yield. Alternatively the dibromide from thereaction with NBS could be poured into DMSO (10-20% concentration byweight) and stirred for 30 minutes at room temperature. When thereaction was deemed complete it was poured into water and the resultingprecipitate was isolated by filtration, the cake was washed with waterand dried to yield an essentially quantitative yield.

[0861] Step 5: To a solution of the indole from above (0.52 g, 1 mmol)in CH₃NO₂ (6.2 mL) was added NH₄OAC (0.077 g, 1 mmol), the mixture washeated to reflux for 1 h, NH₄OAc (0.077 g, 1 mmol) was then added,heating at reflux was continued for an additional 1 h, NH₄Oac (0.077 g,1mmol) was added again and the heating continued for further 1 h. Thereaction mixture was allowed to attain room temperature, EtOAc (50 mL)was added, followed by the addition of 1 00 mL water. The aqueous layerwas extracted with EtOAc, and the combined organic layers were washedwith brine, dried (Na₂SO₄), and evaporated to a yellow foam, which wassubjected to chromatographic purification using 10% EtOAc/hexanes as aneluent to yield4-{3-[1-Benzhydryl-2-(2-nitro-vinyl)-1H-indol-3-yl]-propyl}-benzoic acidmethyl ester as a yellow foam in 75% yield (0.38 g).

[0862] Step 6: Zn(Hg) was made by adding HgCl₂ (3.4 g, 7.2 mmol) to amixture of Zn-dust (34.68 g, 530.35 mmol) and 5% HCl (38 mL) in a 100 mLbeaker, this mixture was stirred vigorously for 10 min. Aqueous phasewas decanted and added 38 mL of 5% HCl again and the mixture was stirredfor 10 min. Aqueous phase was decanted. This solid was added to thevinyl nitro compound 6 (15 g, 26.57 mmol) in THF (660 mL) and conc. HCl(64.5 mL). This mixture was stirred at room temperature for 1 h, then atreflux for 15 min. The reaction mixture was cooled to room temperatureand filtered through celite. Aq. NH₄OH solution (200 mL) was added tothe filtrate, stirred for 15 min and THF was removed under reducedpressure. The aqueous layer was extracted with CH₂Cl₂, combined organiclayer was washed with brine, dried (Na2SO4) and concentrated to a brownfoam, which was purified by column chromatography by eluting the columnwith CHCl₃ in the beginning to remove non-polar impurities then with 2%MeOH/CHCl₃ to isolate the desired4-{3-[2-(2-Amino-ethyl)-1-benzhydryl-1H-indol-3-yl]-propyl)-benzoic acidmethyl ester in 40% yield (6.1 g)

[0863] Step 7: To the amine(1.0 equiv.) and sat. NaHCO₃ (0.14 M) inCH₂Cl₂ (0.07 M) was added 2-Chloro-benzenesulfonyl chloride (1.0equiv.). After 1 h the mixture was poured into saturated sodiumbicarbonate and extracted with CH₂Cl₂. The combined organic phase waswashed with brine, dried over sodium sulfate and purified by columnchromatography to afford 92% of the desired4-(3-{1-Benzhydryl-2-[2-(2-chloro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid methyl ester.

[0864] Step 8: The resulting ester was hydrolyzed by stirring with 1 NNaOH (5 equiv.) in THF (0.07 M) and enough MeOH to produce a clearsolution. The reaction was monitored by TLC (10% MeOH—CH₂Cl₂) for thedisappearance of starting material. The mixture was stirred overnight atroom temperature and then. concentrated, diluted with H₂O, and acidifiedto pH 2-4 using 1 M HCl. The aqueous phase was extracted with EtOAc andthe organic phase was washed with brine, dried over sodium sulfate, andconcentrated to afford the title compound in 56% yield. m/z (M−1) 663.2

EXAMPLE 2964-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid

[0865] Step 1: [(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.07 g,0.24 mmol) was added to a mixture of ethyl4-{2-[2-(2-Aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-fluoro-benzoate(Step 6, Example 190, 0.17 g, 0.2 mmol) and K₂CO₃ (0.055 g, 0.4 mmol) inCH₂Cl₂ (2 mL) and water (0.7 mL) with stirring. After 2 hour at roomtemperature, the mixture was extracted with CH₂Cl₂ (10 mL) and theextract was washed with 0.5 N NaOH, and brine and dried over sodiumsulfate. The CH₂Cl₂ solution was filtered through silica gel and thefiltrate was evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.15 g of ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoateas a white solid;. mp 83-85° C.; HRMS: calcd for C₄₁H₃₆Cl₃FN₂O₅S,792.1395; found (ESI+), 793.14729.

[0866] Step 2: Ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate(0.11 g, 0.14 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.10 g of4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid as a white solid; mp 117-119° C.; HRMS: calcd for C₃₉H₃₂Cl₃FN₂O₅S,764.1082; found (ESI+), 787.09794

EXAMPLE 2974-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid

[0867] Step 1: [(2-chlorophenyl)methyl]sulfonyl chloride (0.14 g, 0.6mmol) was added to a mixture of ethyl4-{2-[2-(2-Aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate(Step 6, Example 190, 0.12 g, 0.2 mmol) and K₂CO₃ (0.11 g, 0.8 mmol) inCH₂Cl₂ (2 mL) and water (1 mL) with stirring. After 2 hour at roomtemperature, the mixture was extracted with CH₂Cl₂ (10 mL) and theextract was washed with 0.5 N NaOH, and brine and dried over sodiumsulfate. The CH₂Cl₂ solution was filtered through silica gel and thefiltrate was evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.07 g of ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoateas a white solid.

[0868] Step 2: Ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate(0.06 g, 0.1 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.06 g of4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid as an off-white solid; mp 132-135° C.; MS (ESI) m/z 729.74((M−H)−); HRMS: calcd for C₃₉H₃₃Cl₂FN₂O₅S, 730.1471; found (ESI+),731.15514.

EXAMPLE 2983-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoicacid

[0869] Step 1: [(3,4-chlorophenyl)methyl]sulfonyl chloride (0.06 g, 0.2mmol) was added to a mixture of ethyl3-(4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-phenyl)-2,2-dimethyl-propionate(0.09 g, 0.14 mmol) and K₂CO₃ (0.04 g, 0.28 mmol) in CH₂Cl₂ (2 mL) andwater (0.7 mL) with stirring. After 2 hour at room temperature, themixture was extracted with CH₂Cl₂ (10 mL) and the extract was washedwith 0.5 N NaOH, and brine and dried over sodium sulfate. The CH₂Cl₂solution was filtered through silica gel and the filtrate wasevaporated. The resulting residue was triturated with a mixture of etherand hexanes to give 0.04 g of ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoateas a white solid.

[0870] Step 2: Ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate(0.04 g, 0.05 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.04 g of3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoicacid as a white solid; mp 207-208° C.; MS (ESI) m/z 849.1 (M−H); HRMS:calcd for C₄₃H₄₁Cl₃N₂O₆S₂, 850.1472; found (ESI+), 851.1545.

EXAMPLE 2994-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoicacid

[0871] Step 1: 2,4-Dihydroxy-benzoic acid methyl ester (11.76 g, 70mmol) was dissolved in Et₂O (175 mL). Then Et₃N (10.78 mL, 77 mmol),Ac₂O (7.28 mL, 77 mmol), and DMAP (catalytic amount) were added. Thereaction solution was then stirred for one hour at room temperature.Then the reaction solution was concentrated by rotary evaporation andthe resulting residue was purified with a silica gel column anddichloromethane as eluent. Obtained 3.44 g 4-Acetoxy-2-hydroxy-benzoicacid methyl ester in 23% yield.

[0872] Step 2: MeOH (0.3 mL, 7.4 mmol) was added to the product fromstep 1 (0.962 g, 4.6 mmol), Ph₃P (1.79 g, 6.8 mmol), and dichloromethane(10 mL). Then DEAD (1.32 mL, 8.4 mmol) was added to the reaction.Reaction was stirred at room temperature for 4 days. Reaction solutionwas concentrated by rotary evaporation and the resulting residue waspurified with silica gel prep plates and 1:3 EtOAc/Hexane as eluent.Obtained 1.10 g of 4-Acetoxy-2-methoxy-benzoic acid methyl ester inquantitative yield.

[0873] Step 3: 0.1N NaOH (10 mL, 1 mmol) was added to a solution of theproduct of step 2 (1.10 g, 4.9 mmol) in THF (1 mL) and MeOH (1 mL).Reaction was stirred for three days at room temperature. Reactionsolution was concentrated by rotary evaporation and resulting residuewas dissolved in water. The solution was neutralized with 1N HCl and aprecipitate formed. Collected precipitate and washed with water andhexane. Obtained 0.29 g of 4-Hydroxy-2-methoxy-benzoic acid methyl esterin 33% yield.

[0874] Step 4:2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142, 0.503 g, 0.78 mmol) was added to a mixture ofHydroxy-2-methoxy-benzoic acid methyl ester (0.29 g, 1.6 mmol), Ph₃P(0.312 g, 1.2 mmol), and dichloromethane (10 mL). Then DEAD (0.2 mL, 1.3mmol) was added to the reaction. Reaction was stirred at roomtemperature overnight. Reaction solution was concentrated by rotaryevaporation and the resulting residue was purified with silica gel prepplates and dichloromethane as eluent. Obtained 0.25 g of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-methoxy-benzoicacid methyl ester in 40% yield.

[0875] Step 5: TBAF (1M in THF) (0.37 mL, 0.37 mmol) was added to asolution of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-methoxy-benzoicacid methyl ester (0.25 g, 0.31 mmol) in THF (4 mL). Reaction wasstirred at room temperature for 30 minutes. Reaction solution wasconcentrated by rotary evaporation and the resulting residue waspurified with silica gel prep plates and 1:9 EtOAc/dichloromethane aseluent. Obtained 0.11 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester (white solid) in 62% yield.

[0876] Step 6: MeSO₂Cl (0.03 mL, 0.39 mmol) and Et₃N (0.07 mL, 0.48mmol) were added to a solution of the alcohol from step 5 (0.11 g, 0.19mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C.for one hour and then warmed to room temperature and stirred anadditional hour. Reaction solution was concentrated by rotaryevaporation. Obtained 0.123 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in quantitative yield.

[0877] Step 7: The mesylate from above (0.123 g, 0.19 mmol) wasdissolved in DMF (5 mL). NaN₃ (0.065 g, 1.0 mmol) was added and themixture was heated to 60° C. and stirred for three hours. Reaction wascooled to room temperature and water was added. Extracted with EtOAc andwashed organic layer with brine. Dried organics over sodium sulfate andfiltered and concentrated by rotary evaporation. Dried further under astrong vacuum. Obtained 0.110 g of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in 97% yield.

[0878] Step 8: Ph₃P (polymer support: 3 mmol Ph₃P/gram) (0.110 g, 0.33mmol) was added to a solution of the azide from step 7 (0.110 g, 0.18mmol) in THF (2 mL). Reaction was stirred at room temperature for 24hours. Then water (0.5 mL) was added and reaction was stirred at roomtemperature overnight. Reaction solution was filtered and the filtratewas concentrated by rotary evaporation. The resulting residue waspurified with silica gel prep plates and 2% MeOH in dichloromethane aseluent. Obtained 0.012 g of4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in 12% yield.

[0879] Step 9: An aqueous, saturated solution of Na₂CO₃ (2 mL) was addedto a solution of the amine from step 8 (0.012 g, 0.021 mmol) and[(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.010 g, 0.039 mmol) indichloromethane (2 mL). Reaction was stirred at room temperature for twohours. The reaction solution was then separated and the organic phasewas collected and washed with brine and dried over sodium sulfate.Filtered and concentrated the organic solution by rotary evaporation.The resulting residue was purified with silica gel prep plates and 2%MeOH in dichloromethane as eluent. Obtained 0.016 g of the desiredsulfonamide (white solid) in 96% yield. m/z (M+1)793

[0880] Step 10: 1N NaOH (1 mL) was added to a solution of the ester fromstep 9 (0.016 g, 0.020 mmol) in THF (1 mL) and MeOH (1 mL). Reaction wasstirred at room temperature for five days. The THF and MeOH were removedby rotary evaporation. Extracted with dichloromethane and separated andcollected the aqueous layer. Neutralized the aqueous layer with 1N HCland collected the resulting precipitate. Obtained 0.013 g of the titleacid (yellow solid) in 84% yield. m/z (M−1)777

EXAMPLE 3004-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoicacid

[0881] Step 1: Isopropanol (0.63 mL, 8.2 mmol) was added to a mixture of4-Acetoxy-2-methoxy-benzoic acid methyl ester (Step 1, Example 299, 1.18g, 5.6 mmol), Ph₃P (1.84 g, 7.0 mmol), and dichloromethane (15 mL). ThenDEAD (1.12 mL, 7.1 mmol) was added to the reaction. Reaction was stirredat room temperature for two days. Reaction solution was concentrated byrotary evaporation and the resulting residue was purified with silicagel prep plates and 1:5 EtOAc/Hexane as eluent. Obtained 1.11 g of4-Acetoxy-2-isopropoxy-benzoic acid methyl ester in 79% yield.

[0882] Step 2: 0.1N NaOH (10 mL, 1 mmol) was added to a solution of4-Acetoxy-2-isopropoxy-benzoic acid methyl ester (0.910 g, 3.6 mmol) inTHF (1 mL) and MeOH (1 mL). Reaction was stirred for three days at roomtemperature. Reaction solution was concentrated by rotary evaporationand resulting residue was dissolved in water. The solution wasneutralized with 1N HCl and a precipitate formed. Collected precipitateand washed with water and hexane. Obtained 0.870 g of4-Hydroxy-2-isopropoxy-benzoic acid methyl ester in quantitative yield.

[0883] Step 3:2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142, 0.500 g, 0.78 mmol) was added to a mixture of4-Hydroxy-2-isopropoxy-benzoic acid methyl ester (0.328 g, 1.6 mmol),Ph₃P (0.312 g, 1.2 mmol), and dichloromethane (10 mL). Then DEAD (0.2mL, 1.3 mmol) was added to the reaction. Reaction was stirred at roomtemperature overnight. Reaction solution was concentrated by rotaryevaporation and the resulting residue was purified with silica gel prepplates and dichloromethane as eluent. Obtained 0.20 g of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-isopropoxy-benzoicacid methyl ester in 31% yield.

[0884] Step 4: TBAF (1M in THF) (0.29 mL, 0.29 mmol) was added to asolution of the silyl ether from step 3 (0.20 g, 0.24 mmol) in THF (4mL). Reaction was stirred at room temperature for 30 minutes. Reactionsolution was concentrated by rotary evaporation and the resultingresidue was purified with silica gel prep plates and 1:9EtOAc/dichloromethane as eluent. Obtained 0.10 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester (brown solid) in 70% yield.

[0885] Step 5: Methane sulfonyl chloride (0.03 mL, 0.39 mmol) and Et₃N(0.06 mL, 0.43 mmol) were added to a solution of the alcohol from Step 4(0.10 g, 0.17 mmol) in dichloromethane (8 mL) at 0° C. Reaction wasstirred at 0° C. for one hour and then warmed to room temperature andstirred an additional hour. Reaction solution was concentrated by rotaryevaporation. Obtained 0.115 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in quantitative yield.

[0886] Step 6: The mesylate from Step 5 (0.115 g, 0.17 mmol) wasdissolved in DMF (5 mL). NaN₃ (0.065 g, 1.0 mmol) was added and themixture was heated to 60° C. and stirred for three hours. Reaction wascooled to room temperature and water was added. Extracted with EtOAc andwashed organic layer with brine. Dried organics over sodium sulfate andfiltered and concentrated by rotary evaporation. Dried further under astrong vacuum. Obtained 0.100 g of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in 94% yield.

[0887] Step 7: Ph₃P (polymer support: 3 mmol Ph₃P/gram) (0.100 g, 0.30mmol) was added to a solution of the azide from Step 6 (0.100 g, 0.16mmol) in THF (2 mL). Reaction was stirred at room temperature for 24hours. Then water (0.5 mL) was added and reaction was stirred at roomtemperature overnight. Reaction solution was filtered and the filtratewas concentrated by rotary evaporation. The resulting residue waspurified with silica gel prep plates and 2% MeOH in dichloromethane aseluent. Obtained 0.020 g of4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in 21% yield.

[0888] Step 8: An aqueous, saturated solution of Na₂CO₃ (2 mL) was addedto a solution of the amine from Step 7 (0.020 g, 0.034 mmol) and[(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.015 g, 0.058 mmol) indichloromethane (2 mL). Reaction was stirred at room temperature for twohours. The reaction solution was then separated and the organic phasewas collected and washed with brine and dried over sodium sulfate.Filtered and concentrated the organic solution by rotary evaporation.The resulting residue was purified with silica gel prep plates and 2%MeOH in dichloromethane as eluent. Obtained 0.022 g of the desiredsulfonamide (white solid) in 79% yield. m/z (M+1)821

[0889] Step 9: 1N NaOH (1 mL) was added to a solution of the ester fromStep 8 (0.022 g, 0.027 mmol) in THF (1 mL) and MeOH (1 mL). Reaction wasstirred at room temperature for five days. The THF and MeOH were removedby rotary evaporation. Extracted with dichloromethane and separated andcollected the aqueous layer. Neutralized the aqueous layer with 1N HCland collected the resulting precipitate. Obtained 0.021 g of the titleacid (yellow solid) in 96% yield. m/z (M−1)805

[0890] Activity Assay

[0891] Coumarine Assay

[0892] 7-hydroxycoumarinyl 6-heptenoate was used as a monomericsubstrate for cPLA2 as reported previously (Huang, Z. et al., 1994,Nalytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 μLassay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 60 μM7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4μg cPLA2 in 50 μL assay buffer. Hydrolysis of the 7-hydroxycounarimyl6-heptenoate ester was monitored in a fluorometer by exciting at 360 nmand monitoring emission at 460 nm. Enzyme activity is proportional tothe increase in emission at 460 nm per minute. In the presence of acPLA2 inhibitor, the rate of increase is less. Coumarin Example # IC₅₀(uM) Example 1 0.42 Example 2 2 Example 3 2.5 Example 4 56 Example 5 3Example 6 2.0 Example 7 0.55 Example 8 2 Example 9 0.7 Example 10 0.57Example 11 0.45 Example 12 150 Example 13 0.64 Example 14 0.8 Example 150.63 Example 16 0.98 Example 17 0.2 Example 18 0.4 Example 19 0.31Example 20 1.1 Example 21 1.1 Example 22 1.8 Example 23 1.5 Example 240.34 Example 25 3.4 Example 26 1.1 Example 27 0.8 Example 28 0.95Example 29 0.19 Example 30 0.15 Example 31 0.15 Example 32 0.085 Example33 2.9 Example 35 0.33 Example 36 0.5 Example 37 0.37 Example 38 0.5Example 39 0.32 Example 40 0.73 Example 41 0.2 Example 42 0.18 Example43 0.2 Example 44 0.25 Example 45 4.7 Example 46 4.8 Example 47 0.58Example 48 2.35 Example 49 1.1 Example 50 0.69 Example 51 2.2 Example 520.13 Example 53 0.37 Example 54 0.31 Example 55 0.26 Example 56 0.13Example 57 0.28 Example 58 0.36 Example 59 0.29 Example 60 0.15 Example61 0.34 Example 62 0.38 Example 63 0.30 Example 64 0.12 Example 65 0.13Example 66 0.15 Example 67 0.14 Example 68 0.16 Example 69 0.15 Example70 0.18 Example 71 0.45 Example 72 0.28 Example 73 0.30 Example 74 0.28Example 75 0.4 Example 76 0.4 Example 77 0.48 Example 78 0.34 Example 790.15 Example 80 3.7 Example 81 0.47 Example 82 0.5 Example 83 0.45Example 84 0.5 Example 85 0.4 Example 86 0.6 Example 87 1.2 Example 88<7.4 Example 89 0.38 Example 90 0.65 Example 91 0.5 Example 92 1.0Example 93 0.56 Example 94 0.8 Example 95 0.85 Example 96 0.95 Example97 0.95 Example 98 1.1 Example 99 1.0 Example 100 0.12 Example 101 0.1Example 102 0.19 Example 103 1.1 Example 104 1.1 Example 105 0.65Example 106 0.22 Example 107 0.33 Example 108 0.15 Example 109 0.4Example 110 0.5 Example 111 1.0 Example 112 1.2 Example 113 1.3 Example114 1.1 Example 115 0.9 Example 116 1.2 Example 117 1.6 Example 118 0.4Example 119 0.4 Example 120 0.4 Example 121 0.46 Example 122 2.5 Example123 1.5 Example 124 0.8 Example 125 1.4 Example 126 0.2 Example 127 0.2Example 128 0.32 Example 129 0.13 Example 130 0.17 Example 131 0.2Example 132 0.2 Example 133 0.09 Example 134 >1 Example 135 0.2 Example136 0.18 Example 137 NT Example 138 0.2 Example 139 1.7 Example 140 0.2Example 141 0.17 Example 142 NT Example 143 NT Example 144 NT Example145 NT Example 146 NT Example 147 NT Example 148 NT Example 149 NTExample 150 NT Example 151 NT Example 152 0.32 Example 153 0.16 Example154 0.35 Example 155 0.45 Example 156 0.16 Example 157 0.2 Example 1580.2 Example 159 0.65 Example 160 0.19 Example 161 0.32 Example 162 1.0Example 163 0.3 Example 164 0.2 Example 165 0.53 Example 166 0.4 Example167 0.19 Example 168 0.27 Example 169 0.46 Example 170 0.95 Example 1710.36 Example 172 0.35 Example 173 0.4 Example 174 1.1 Example 175 0.37Example 176 0.4 Example 177 0.9 Example 178 0.65 Example 179 0.9 Example180 0.23 Example 181 0.32 Example 182 0.6 Example 183 0.17 Example 1840.35 Example 185 0.17 Example 186 0.1 Example 187 0.2 Example 188 NTExample 189 NT Example 190 0.53 Example 191 0.2 Example 192 <3.7 Example193 1.8 Example 194 1 Example 195 1 Example 196 0.56 Example 197 0.4Example 198 0.7 Example 199 0.45 Example 200 0.35 Example 201 0.35Example 202 0.3 Example 203 0.69 Example 204 0.2 Example 205 0.37Example 206 0.5 Example 207 1.4 Example 208 0.24 Example 209 0.35Example 210 0.15 Example 211 0.4 Example 212 0.18 Example 213 0.45Example 214 NT Example 215 NT Example 216 NT Example 217 2.6 Example 2180.14 Example 219 0.4 Example 220 0.4 Example 221 0.5 Example 222 0.19Example 223 0.6 Example 224 0.25 Example 225 0.4 Example 226 0.14Example 227 0.16 Example 228 0.4 Example 229 0.5 Example 230 0.15Example 231 0.25 Example 232 0.13 Example 233 0.34 Example 234 0.23Example 235 0.18 Example 236 0.085 Example 237 0.2 Example 238 0.25Example 239 0.48 Example 240 0.32 Example 241 0.54 Example 242 1.3Example 243 0.75 Example 244 1.3 Example 245 0.9 Example 246 1.2 Example247 1.2 Example 248 1.2 Example 249 0.67 Example 250 2.1 Example 251 1.5Example 252 0.73 Example 253 0.75 Example 254 0.26 Example 255 0.5Example 256 0.6 Example 257 0.5 Example 258 0.8 Example 259 0.2 Example260 0.37 Example 261 0.25 Example 262 0.53 Example 263 0.32 Example 2640.4 Example 265 0.37 Example 266 0.16 Example 267 0.074 Example 268 0.09Example 269 0.15 Example 270 0.14 Example 271 0.15 Example 272 0.1Example 273 0.11 Example 274 NT Example 275 0.24 Example 276 0.32Example 277 0.6 Example 278 1.9 Example 279 0.16 Example 280 0.35Example 281 NT Example 282 NT Example 283 0.5 Example 284 0.4 Example285 NT Example 286 NT Example 287 0.42 Example 288 0.4 Example 289 0.9Example 290 NT Example 291 NT Example 292 NT Example 293 NT Example 294NT Example 295 0.55 Example 296 0.32 Example 297 0.3 Example 298 0.19Example 299 1.0 Example 300 >2

[0893] The compounds of the invention inhibit cPLA2 activity that isrequired for supplying arachidonic acid substrate to cyclooxygenase-1or2 and 5-lipoxygenase, which in turn initiate the production ofprostaglandins and leukotrienes respectively. In addition, cPLA2activity is essential for producing the lyso-phospholipid that is theprecursor to PAF. Thus these compounds are useful in the treatment andprevention of disease states in which leukotrienes, prostaglandins orPAF are involved. Moreover, in diseases where more than one of theseagents plays a role, a cPLA2 inhibitor would be expected to be moreefficacious than leukotriene, prostaglandin or PAF receptor antagonistsand also more effective than cyclooxygenase or 5-lipoxygenaseinhibitors.

[0894] Therefore, the compounds, pharmaceutical compositions andregimens of the present invention are useful in treating and preventingthe disorders treated by cyclooxygenase-2, cycloxygenase-1, and5-lipoxygenase inhibitors and also antagonists of the receptors for PAF,leukotrienes or prostaglandins. Diseases treatable by compounds of thisinvention include but are not limited to: pulmonary disorders includingdiseases such as asthma, chronic bronchitis, and related obstructiveairway diseases; allergies and allergic reactions such as allergicrhinitis, contact dermatitis, allergic conjunctivitis, and the like;inflammation such as arthritis or inflammatory bowel diseases, skindisorders such as psoriasis, atopic eczema, acne, UV damage, burns anddermatittis; cardiovascular disorders such as atherosclerosis, angina,myocardial ischaemia, hypertension, platelet aggregation, and the like;and renal insufficiency induced by immunological or chemical. The drugsmay also be cytoprotective, preventing damage to the gastrointestinalmucosa by noxious agents. The compounds will also be useful in thetreatment of adult respiratory distress syndrome, endotoxin shock andischeamia induced injury including myocardial or brain injury.

[0895] The methods of treatment, inhibition, alleviation or relief ofasthma of this invention include those for Extrinsic Asthma (also knownas Allergic Asthma or Atopic Asthma), Intrinsic Asthma (also known asNonallergic Asthma or Nonatopic Asthma) or combinations of both, whichhas been referred to as Mixed Asthma. The methods for those experiencingor subject to Extrinsic or Allergic Asthma include incidents caused byor associated with many allergens, such as pollens, spores, grasses orweeds, pet danders, dust, mites, etc. As allergens and other irritantspresent themselves at varying points over the year, these types ofincidents are also referred to as Seasonal Asthma. Also included in thegroup of Extrinsic Asthmas is bronchial asthmas and allergicbronchopulminary aspergillosis.

[0896] Intrinsic Asthmas that may be treated or alleviated by thepresent methods include those caused by infectious agents, such as coldand flu viruses in adults and respiratory syncytial virus (RSV),rhinovirus and influenza viruses common in children. Also included arethe asthma conditions which may be brought about in some asthmatics byexercise and/or cold air. The methods are useful for Intrinsic Asthmasassociated with industrial and occupational exposures, such as smoke,ozone, noxious gases, sulfur dioxide, nitrous oxide, fumes, includingisocyanates, from paint, plastics, polyurethanes, varnishes, etc., wood,plant or other organic dusts, etc. The methods are also useful forasthmatic incidents associated with food additives, preservatives orpharmacological agents. Common materials of these types are foodcoloring such as Tartrazine, preservatives like bisulfites andmetabisulfites, and pharmacological agents such as aspirin andnon-steroidal anti-inflammatory agents (NSAIDs). Also included aremethods for treating, inhibiting or alleviating the types of asthmareferred to as Silent Asthma or Cough Variant Asthma.

[0897] The methods herein are also useful for treatment and alleviationof Intrinsic Asthma associated with gastroesophageal reflux (GERD),which can stimulate bronchoconstriction. GERD, along with retainedbodily secretions, suppressed cough, and exposure to allergens andirritants in the bedroom can contribute to asthmatic conditions and havebeen collectively referred to as Nighttime Asthma or Nocturnal Asthma.In methods of treatment, inhibition or alleviation of asthma associatedwith GERD, a pharmaceutically effective amount of the compounds of thisinvention may be used as described herein in combination with apharmaceutically effective amount of an agent for treating GERD. Theseagents include, but are not limited to, proton pump inhibiting agentslike PROTONIX® brand of delayed-release pantoprazole sodium tablets,PRILOSEC® brand omeprazole delayed release capsules, ACIPHEX® brandrebeprazole sodium delayed release tablets or PREVACID® brand delayedrelease lansoprazole capsules.

[0898] The compounds of this invention may also be administered in themethods of this invention with analgesic and anti-inflammatory agentssuch as NSAIDs and aspirin and other salicylates. Examples of usefulagents include ibuprofen (MOTRIN®, ADVIL®), naproxen (NAPROSYN®),sulindac (CLINORIL®), diclofenac (VOLTAREN®), piroxicam (FELDENE®)ketoprofen (ORUDIS®), diflunisal (DOLOBID®), nabumetone (RELAFEN®),etodolac (LODINE®), oxaprozin (DAYPRO®), indomethacin (INDOCIN®),melicoxam (MOBICOX®), valdecoxib and eterocoxib. Aspirin isanti-inflammatory when given in high doses, otherwise it is just a painkiller like acetaminophen (TYLENOL®).

[0899] Suitable cyclooxygenase 2 (COX-2) inhibitors for use with themethods of this invention include, but are not limited to,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,CDC-501, celecoxib, COX-189,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, CS-179,CS-502, D-1367, darbufelone, DFP, DRF-4367, flosulide, JTE-522(4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),L-745337, L-768277, L-776967, L-783003, L-791456, L-804600, meloxicam,MK663 (etoricoxib), nimesulide, NS-398, parecoxib,1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl) cyclobutenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, Pharmaprojects No. 6089 (Kotobuki Pharmaceutical),RS-113472, RWJ-63556, S-2474, S-33516, SC-299, SC-5755, valdecoxib,UR-8877, UR-8813, UR-8880. Further suitable COX-2 inhibitors for useaccording to the invention include parecoxib, MK663,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide(JTE-522), nimesulide, flosulide, DFP and2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,and their physiologically acceptable salts, esters or solvates.

[0900] Each of the methods of this invention comprises administering toa mammal in need of such treatment a pharmaceutically or therapeuticallyeffective amount of a compound of this invention. In the instances ofcombination therapies described herein, it will be understood theadministration further includes a pharmaceutically or therapeuticallyeffective amount of the second pharmaceutical agent in question. Thesecond or additional pharmacological agents described herein may beadministered in the doses and regimens known in the art.

[0901] The compounds of this invention may also be used in comparableveterinary methods of treatment, particularly for the veterinarytreatment, inhibition or alleviation of inflammation and pain associatedwith asthmatic conditions. These methods will be understood to be ofparticular interest for companion mammals, such as dogs and cats,particularly with feline asthma. These compounds may also be used in thetreatment of inflammation of the air passages, such as in conditions ofasthma, laryngitis, tracheitis, bronchitis, rhinitis and pharyngitis

[0902] The compounds of this invention may be used in the veterinarytreatment of asthma and asthmatic conditions in combination with othertreatments for asthma, such as feline asthma, including oral orinjectable steroids, Cyproheptadine, Cyclosporin A, orAnti-Interleukin-5 Antibody.

[0903] Each of these veterinary methods comprises administering to themammal in need thereof a pharmaceutically effective amount of a compoundof this invention, or a pharmaceutically acceptable salt form thereof.The compounds of this invention may be used for human or veterinarymethods in conjunction with other medicaments or dietary supplementsknown in the art for the treatment, inhibition or alleviation ofinflammation or pain. These may include aspirin (including bufferedaspirin, aspirin with Maalox and enteric coated aspirin), COX-2inhibitors, such as celecoxib, non-acetylated carboxylic acids, such asmagnesium salicylate, salicylamide or sodium salicylate, acetic acids,such as doclofenac or etodolac, propionic acids, such as ibuprofen,naproxen (available in NAPROSYN® and EQUIPROXEN® brands), ketoprofen,RIMADYL® (carprofen), flunixin meglumine, fenamic acids, such astolfenamic acid, mefanamic acid, meclofenamic acid (ARQUEL®) or niflumicacid, enolic acids, such as oxyphenbutazone, phenylbutazone, piroxicamor dipyrone, or non-acidic compounds like nabumetone. Also used inveterinary applications are dimethylsulfoxide (DMSO), orgotein (such asPALOSEIN® brand of orgotein), polysulfated glycosaminoglycans or PS-GAGs(such as ADEQUAN® brand polysulfated glycosaminoglycan), hyaluronic acidand its natural and synthetic analogues, Ketorolac trimethamine (such asthe TORADOL® brand), FELDENE® (piroxicam), or METACAM® (meloxicam).

[0904] Dietary supplements used in human or veterinary applicationsinclude glucosamines, chondroitin sulfate, methylsulfonylmethane (MSM),and omega 3 fatty acids and other cold water fish oils. The compoundsand methods of this invention may also be used in conjunction with humanor veterinary physical therapy, massage, chiropractic and accupuncturetreatments and regimens. Each of these medicaments and dietarysupplements may be administered to the mammal in question using regimensand effective dosages known in the art.

What is claimed
 1. Amethod of treatment of asthma in a mammal, themethod comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of the formula:

wherein: R is selected from the formulae —(CH₂)_(n)—A, —(CH₂)_(n)—S—A,or —(CH₂)_(n)—O—A, wherein A is selected from the moieties:

D is C₁-C₆ lower alkyl, C₁-C₆ lower alkoxy, C₃-C₆ cylcoalkyl, —CF₃ or—(CH₂)₁₋₃—CF₃; B and C are independently selected from phenyl,pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, eachoptionally substituted by from 1 to 3, preferably 1 to 2, substituentsselected independently from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH,—C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, or by a 5- or 6-membered heterocyclic orheteroaromatic ring containing 1 or 2 heteroatoms selected from O, N orS; or n is an integer from 0 to 3; n₁ is an integer from 1 to 3; n₂ isan integer from 0 to 4; n₃ is an integer from 0 to 3; n₄ is an integerfrom 0 to 2; X₁ is selected from a chemical bond, —S—, —O—, —S(O)—,—S(O)₂—, —NH—, —NHC(O)—, —C═C—,

R₁ is selected from C₁-C₆ alkyl, C₁-C₆ fluorinated alkyl, C₃-C₆cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN, —N(C₁-C₆alkyl)₂, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, napthyl,morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl,imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazole,indole, benzoxazole, benzofuran, imidazolidine-2-thione,7,7,dimethyl-bicyclo[2.2.1]heptan-2-one, Benzo[1,2,5]oxadiazole,2-Oxa-5-aza-bicyclo[2.2.1]heptane, Piperazin-2-one or pyrrolyl groups,each optionally substituted by from 1 to 3, preferably 1 to 2,substituents independently selected from H, halogen, —CN, —CHO, —CF₃,OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —SO₂(C₁-C₃ alkyl, —SO₂NH₂, —SO₂NH(C₁-C₃ alkyl),—SO₂N(C₁-C₃ alkyl)₂, —COOH, —CH₂—COOH, —CH₂—N(C₁-C₆ alkyl), —CH₂—N(C₁-C₆alkyl)₂, —CH₂—NH₂, pyridine, 2-Methyl-thiazole, morpholino,1-Chloro-2-methyl-propyl, —C₁-C₆thioalkyl, phenyl (further optionallysubstituted with halogens), benzyloxy, (C₁-C₃ alkyl)C(O)CH₃, (C₁-C₃alkyl)OCH₃, C(O)NH₂, or

X₂ is selected from —O—, —CH₂—, —S—, —SO—, —SO₂—, —NH—, —C(O)—,

R₂ is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl,thienyl or pyrrolyl groups, the ring moiety being substituted by a groupof the formula —(CH₂)n₄—CO₂H or a pharmaceutically acceptable acid mimicor mimetic; and also optionally substituted by 1 or 2 additionalsubstituents independently selected from H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂,—N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; R₃ is selected from H,halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; R₄ isselected from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —N—C(O)—N(C₁-C₃ alkyl)₂, —N—C(O)—NH(C₁-C₃ alkyl),—N—C(O)—O—(C₁-C₃ alkyl), —SO₂—C₁-C₆ alkyl, —S—C₃-C₆ cycloalkyl,—S—CH₂—C₃-C₆ cycloalkyl, —SO₂—C₃-C₆ cycloalkyl, , —SO₂—CH₂—C₃-C₆cycloalkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, —O—C₃-C₆cycloalkyl, , —O—CH₂—C₃-C₆ cycloalkyl, phenyl, benzyl, benzyloxy,morpholino or other heterocycles such as pyrrolidino, piperidine,piperizine furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone,pyrazole, imidazole, oxazole or isoxazole, the rings of each of these R₄groups each being optionally substituted by from 1 to 3 substituentsselected from the group of H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆),—NO₂, —SO₂(C₁-C₃ alkyl), —SO₂NH(C₁-C₃ alkyl), —SO₂N(C₁-C₃ alkyl)₂, orOCF₃; or a pharmaceutically acceptable salt form thereof.
 2. A method ofclaim 1 wherein the pharmaceutically acceptable acid mimics or mimeticsinclude those wherein R₂ is selected from the group consisting of:

wherein R_(a) is selected from —CF₃, —CH₃, phenyl, or benzyl, with thephenyl or benzyl groups being optionally substituted by from 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —CF₃,halogen, —OH, or —COOH; R_(b) is selected from —CF₃, —CH₃, —NH₂, phenyl,or benzyl, with the phenyl or benzyl groups being optionally substitutedby from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —CF₃, halogen, —OH, or —COOH; and R_(c) is selected from —CF₃or C₁-C₆ alkyl.
 3. A method of claim 1 wherein A is the moiety:

and B, C, n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are asdefined in claim
 1. 4. A method of claim 3 wherein B and C areunsubstituted phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolylgroups and R, n, n1, n2, n3, n4, R₁, X₁, X₂, R₂, R₃, and R₄ are asdefined in claim
 1. 5. A method of claim 1 wherein A is the moiety:

and n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are as defined inclaim
 1. 6. Amethod of treatment of asthma in a mammal, the methodcomprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of formulae (II) or (III):

wherein n1, n2, n3, n4, X₁, X₂, R₁, R₂, R₃, and R₄ are as defined inclaim 1, or a pharmaceutically acceptable salt thereof.
 7. A method ofclaim 6 wherein n3=1, and n, n1, n2, n4, X₁, X₂, R₁, R₂, R₃, and R₄ areas defined in claim 6, or a pharmaceutically acceptable salt thereof. 8.A method of claim 6 wherein R₂ is phenyl substituted by a group of theformula —(CH₂)_(n4)—CO₂H; and optionally substituted by 1 or 2additional substituents independently selected from H, halogen, —CN,—CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂,—N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO; and n1 n2, n4, R₁, X₁,X₂, R₂, R₃, and R₄ are as defined in claim 6, or a pharmaceuticallyacceptable salt thereof.
 9. A method of treatment of asthma in a mammal,the method comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of formulae (IV) or (V):

wherein: n₁ is an integer from 1 to 3; n₂ is an integer from 1 to 3; R₅,R₆ and R₇ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; X₁ is selected from a chemical bond, —S—, —O—,—NH— or —N(C₁-C₃ alkyl)-; X₂ is selected from —O—, —SO₂— or —CH₂—; R₂ isa moiety selected from the group of:

R₈ and R₉ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; n₄ is an integer from 0 to 2; R₃ is selectedfrom H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; andR₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole; or a pharmaceutically acceptable salt form thereof. 10.Amethod of treatment of asthma in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the formulae (VI) or (VII):

wherein: X₁ is selected from a chemical bond, —S—, —O—, —NH— or —N(C₁-C₃alkyl)-; X₂ is selected from —O—, —SO₂—, or —CH₂—; R₃ is selected fromH, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; andR₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole; n₁ is an integer from 1 to 2; n₂ is an integer from 1 to 2;R₅, R₆ and R₇ are independently selected from H, halogen, —CN, —CHO,—CF₃, OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; R₈ and R₉ are independentlyselected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆alkoxy, —NH₂, —N(C_(-C) ₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂; or apharmaceutically acceptable salt form thereof.
 11. A method of claim 10of formulae (VI) or (VII) wherein: n₁ is 1; n₂ is 1; and X₁, X₂, R₃, R₄,R₅, R₆, R₇, R₈ and R₉ are as defined in claim 10, or a pharmaceuticallyacceptable salt form thereof.
 12. A method of claim 1, wherein X₁ is achemical bond and n₁, n₂, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are asdefined in claim 1, or a pharmaceutically acceptable salt form thereof.13. A method of claim 1, wherein X₁ is a chemical bond and B, C, n, n₁,n₂, n₃, n₄, R, X₁, X₂, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are asdefined in claim 1, or a pharmaceutically acceptable salt form thereof.14. A method of claim 6 of formulae (II) or (III) wherein: X₁ is achemical bond and n₁, n₂, n₃, n₄, X₁, X₂, R₁, R₂, R₃ and R₄ are asdefined in claim 1, or a pharmaceutically acceptable salt form thereof.15. A method of claim 9 of formulae (IV) or (V) wherein: X₁ is achemical bond and n₁, n₂, n₄, X₁, X₂, R₂, R₃ and R₄, R₅, R₆, R₇, R₈, R₉are as defined in claim 9, or a pharmaceutically acceptable salt formthereof.
 16. A method of claim 10, wherein X₁ is a chemical bond and n₁,n₂, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are as defined in claim 10, or apharmaceutically acceptable salt form thereof.
 17. A method of claim 1wherein the compound is selected from the group consisting of:4-[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[(isopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid; 4-[2-(1-Benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-2-(2-{[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 18. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 19. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-(2-({[(3-(trifluoromethyl)benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-(2-({[(4-(trifluoromethyl)benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 20. A methodof claim 1 wherein the compound is selected from the group consistingof:2-(2-{[(2-Aminobenzyl)sulfonyl]amino}ethyl)-4-{2-[1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-difluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and3-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoicacid; and a pharmaceutically acceptable salt form thereof.
 21. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)ethyl′1H-indol-3-yl}ethoxy)benzoic acid;4-(2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid; and2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 22. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 23. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-′3-yl)ethoxy]benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 24. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[4-(1piperidinylsulfonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{2-[2-({[4-(Aminosulfonyl)benzyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid; and4-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methanesulfonyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid; and apharmaceutically acceptable salt form thereof.
 25. A method of claim 1wherein the compound is selected from the group consisting of:4-(2-{1-Benzhydryl-5-chloro-2-[2-(4-diethylsulfamoyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-{3-[1-Benzhydryl-5-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-propyl}-benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-(2-[(methylsulfonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 26. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[2-(1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;2-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoicacid; 4-{2-[{1-benzhydryl-5-chloro-2-(2-{[(3-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid; and4-{2-[{1-benzhydryl-5-chloro-2-(2-{[(4-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 27. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[{1-benzhydryl-5-chloro-2-(2-{[(2-(pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indoly-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 28. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonylamino)ethyl]-1H-indol-3-yl}propyl)benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid; and4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 29. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 30. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoicacid; and4-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 31. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-trifluorometoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and a pharmaceutically acceptable salt form thereof.
 32. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloro-2-[pyridinyl)methyl]sulfonylamino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 33. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-benzhydryl-5-chloro-2[2({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dimethyl-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-6-methyl-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 34. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-ylethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-phenylamino-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and a pharmaceutically acceptable salt form thereof.
 35. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and a pharmaceutically acceptable salt form thereof.
 36. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 37. A methodof claim 1 wherein the compound is selected from the group consistingof:4-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(2,6-dimethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl)-1H-indol-3-yl)-propyl]-benzoicacid;4-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-pyrazol-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 38. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 39. A methodof claim 1 wherein the compound is selected from the group consistingof:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(cyanomethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; and4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2,5-dimethyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 40. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-thiomorpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-piperidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-o-tolylsulfanylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-phenylsulfanylmethane-sulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; or4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichloro-phenylsulfanylmethane-sulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid; and apharmaceutically acceptable salt form thereof.
 41. A method of claim 1wherein the compound is selected from the group consisting of:4-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxy-phenylsulfanyl-methanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3-hydroxy-pyrrolidine-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(4-hydroxy-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; and4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 42. A methodof claim 1 wherein the compound is selected from the group consistingof:4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-imidazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;3-[4-({2-[1-Benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid; and3-(4-{[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoicacid; and a pharmaceutically acceptable salt form thereof.
 43. A methodof claim 1 wherein the compound is selected from the group consistingof:3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;4-({[(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl)-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoicacid; and4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3yl)ethyl]sulfonyl}benzoicacid; and a pharmaceutically acceptable salt form thereof.
 44. A methodof claim 1 wherein the compound is selected from the group consistingof:4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid; and4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; and a pharmaceutically acceptable salt form thereof.
 45. A methodof claim 1 wherein the compound is selected from the group consistingof:4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid; and4-[2-(1-benzhydryl-2-{3-[(benzylsulfonyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid; and a pharmaceutically acceptable salt form thereof.